Tesi: "Pain sensitization"

1

McCormick, Emma, e Magdalena Sjöwall. "Central sensitization in orofacial pain". Thesis, Malmö högskola, Odontologiska fakulteten (OD), 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:mau:diva-19833.

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Syfte. Att retrospektivt undersöka relationen mellan central sensitisering i det orofacialaområdet och refererad smärta, som kliniskt fynd, samt psykosociala faktorer hos patienter medDC/TMD-muskeldiagnosen myofasciell smärta med refererad smärta (MPR). Studien syftadeäven till att undersöka skillnader gällande psykosociala faktorer mellan patienter somdiagnostiserats med DC/TMD muskeldiagnoserna myofasciell smärta med refererad smärta(MPR), lokal myalgi (LM) och patienter med orofacial smärta eller käkdysfunktion men ejkäkmuskeldiagnos (WMD) som kontrollgrupper.Material och metod. Information från 85 patienters DC/TMD-undersökning utförd påOrofaciala smärtenheten vid Malmö högskola mellan september 2012 till årsslutet 2013insamlades retrospektivt. Undersökta variabler inkluderade smärtintensitet, smärt-relateraddysfunktion, psykosociala faktorer (depression, ångest och stress) samt refererad smärta.Patienterna indelades i grupper baserade på muskeldiagnos enligt DC/TMD samt utbredning avsmärta. Non-parametrisk statistik användes och P < 0,05 betraktades som signifikant.Resultat. Patienter med MPR uppvisade en signifikant korrelation mellan totala antaletrefererade smärtlokalisationer och smärt-relaterad dysfunktion (rs = 0,43, n = 49, p = 0,002),depression (rs = 0,32, n = 49, p = 0,023) och stress (rs = 0,39, n = 49, p = 0,006). Patienter meden generell smärtutbredning uppvisade en signifikant högre grad av stress (p = 0,020) samt flerantal refererade smärtlokalisationer (p = 0,019) jämfört med patienter med lokal och/ellerregional orofacial smärta.Konklusion. Studien indikerar att grad av central sensitisering kan bedömas med hjälp avutbredningen av refererad smärta, undersökt enligt DC/TMD, hos patienter med diagnosenmyofasciell smärta med refererad smärta i det orofaciala området. Studien kunde inte påvisaskillnader gällande psykosociala faktorer mellan de undersökta grupperna.
Objective. The aim of this study was to retrospectively investigate the relation between referredpain, as a clinical finding, and psychosocial factors versus central sensitization in patients withmyofascial pain with referral (MPR) as assessed according to DC/TMD. The study also aimedto investigate differences regarding psychosocial factors between patients demonstratingmyofascial pain with referral (MPR) and patients diagnosed with the DC/TMD muscle diagnoselocal myalgia (LM) as well as OFP/TMD patients without masticatory muscular diagnose(WMD) as control patients.Material and methods. Patients’ medical records of 85 patients examined at the Orofacial PainUnit at Malmö University during September 2012 till the end of 2013 were retrospectivelyexamined for DC/TMD data. Examined variables included pain intensity, pain-related disability,psychosocial factors (depression, anxiety and stress) and referred pain. The patients weredivided into groups based on DC/TMD muscle diagnosis as well as extension of pain. Nonparametricstatistics were used and a probability level of P < 0.05 was considered as significant.Results. Patients with MPR demonstrated significant correlations between the total number ofreferred pain sites and disability score (rs = 0.43, n = 49, p = 0.002), depression (rs = 0.32, n =49, p = 0.023) as well as stress (rs = 0.39, n = 49, p = 0.006). Patients with generalized paindistribution demonstrated a significantly higher degree of stress (p = 0.020) as well as highernumber of referred pain sites (p = 0.019) than patients with local and/or regional orofacial pain.Conclusion. This study indicates that the degree of central sensitization can be estimated bythe extent of referred pain, as assessed according to DC/TMD, in patients with myofascial painwith referred pain in the orofacial region. This study could not detect a difference inpsychosocial factors between the three groups, myofascial pain with referral (MPR), localmyalgia (LM) and no masticatory muscle diagnosis (WMD).

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2

Seitz, Viola [Verfasser]. "Sensitization and inhibition of pain / Viola Seitz". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2020. http://d-nb.info/1209130866/34.

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3

Schrepf, Andrew David. "Inflammation and central pain sensitization in Interstitial Cystitis/Bladder Pain Syndrome". Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1900.

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Central sensitization refers to abnormal pain modulation present which is characterized by non-aversive or mildly aversive stimuli promoting feelings of pain. Many conditions referred to as Functional Somatic Syndromes (FSS)s are characterized by abnormal pain modulation, including pain in areas of the body not thought to be related to the specific FSS with which the patient has been diagnosed. Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a diagnosis of exclusion characterized by pelvic pain and urologic symptoms that shares many environmental and psychosocial correlates with FSSs. Treatment is generally non-satisfactory for patients despite substantial healthcare expenditures. Preliminary evidence suggests abnormal pain modulation in IC/BPS. Inflammatory dysregulation is an underexplored mechanism in the pain experience in IC/BPS and FSSs. The purpose of the current project is to explore the role of dysregulated inflammatory processes in IC/BPS with an emphasis on painful symptoms in three distinct papers. Paper one examines the role of inflammation in IC/BPS patients with particular emphasis on the association of Toll-Like Receptor (TLR) - 4 mediated inflammation with symptoms of pelvic pain. Paper two expands on the findings of paper one by exploring the association of TLR-4 mediated inflammation with the presence of comorbid FSSs and widespread pain. Paper three evaluates the predictive ability of these previously explored baseline inflammatory measures by testing the association between TLR-2 and 4-mediated inflammation and diurnal cortisol rhythms with symptom trajectories and symptom flares over one year of observation. Finally, the significance of these novel findings is explored.

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4

Janke, Elizabeth Amy. "Psychosocial Correlates of Sensitization in Chronic Pain: An Exploratory Analysis". Ohio University / OhioLINK, 2004. http://www.ohiolink.edu/etd/view.cgi?ohiou1108061243.

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5

Asiedu, Marina N. "Spinal Sensitization Mechanisms Promoting Pain: Gabaergic Disinhibition and Pkmζ-Mediated Plasticity". Diss., The University of Arizona, 2012. http://hdl.handle.net/10150/232496.

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As a major public health problem affecting more that 76.5 million Americans, chronic pain is one main reason why people seek medical attention. It is a pathological nervous system disorder that persists for months or years. Sensitization of nociceptive neurons in the dorsal horn of the spinal cord is crucial in the development of allodynia and hyperalgesia. The work presented in this thesis will focus on spinal protein kinase M zeta (PKMζ)-mediated plasticity and GABAergic disinhibition as spinal amplification mechanisms that orchestrate persistent changes in the dorsal horn of the spinal cord. As a result of central sensitization following peripheral nerve injruy, GABAergic disinhibition occurs due to an alteration in Cl- homeostasis via reduced KCC2 expression and function. Intrathecal administration of acetazolamide (ACT), a carbonic anhydrase inhibitor, attenuated neuropathic allodynia and spinal co-adminitation of ACT and midazolam (MZL), an allosteric modulator of the benzodiazepine class of GABAA receptors, synergistically inhibited neuropathic allodynia. Further studies concerning the impact of altered Cl-homeostasis via reduced KCC2-mediated Cl-extrusion capacity on the analgesic efficacy and potency of GABAA receptor agonist and allosteric modulators revealed that there is a differential regulation of the agonists and allosteric modulators at the GABAA receptor complex when Cl-homeostasis is altered. Another spinal amplification mechanism leading to central sensitization is PKMζ-mediated spinal LTP. In model of persistent nociceptive sensitization, allodynia induced by IL-6 injection or plantar incision was abolished by both the inhibition of protein translation machinery and PKMζ inhibitor, ZIP. However, only PKMζ inhibition prevented the enhanced pain hypersensitivity precipitated by a subsequent stimulus after the initial hypersensitivity had resolved, asserting that spinal PKMζ underlies the maintenance mechanisms of persistent nociceptive sensitization. Also, these results confirmed that the initiation mechanisms of persistent sensitization parallel LTP initiation mechanisms and the maintenance mechanisms of persistent sensitization parallel LTP maintenance mechanisms. Taken together, these results indicate that these amplification mechanisms drive a chronic persistent state in these models such that inhibition of these spinal amplication mechanisms will serve as an effective approach in the quenching chronic pain hypersensitivity in chronic pain models.

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6

Warwick, Charles A. "The role of complement component C5a in nociceptive sensitization". Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5676.

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The complement system is a principal component of innate immunity. Recent studies have underscored the importance of C5a and other complement components in inflammatory and neuropathic pain, although the underlying mechanisms are largely unknown. In particular, it is unclear how the complement system communicates with nociceptors and which ion channels and receptors are involved. Here we demonstrate that inflammatory thermal and mechanical hyperalgesia induced by complete Freund’s adjuvant were accompanied by C5a upregulation and were markedly reduced by C5a receptor (C5aR1) knockout (KO) or treatment with the C5aR1 antagonist PMX53. Direct administration of C5a into the mouse hindpaw produced strong thermal and mechanical hyperalgesia, an effect that was absent in TRPV1 KO mice, and was blocked by the TRPV1 antagonist AMG9810. Immunohistochemistry of mouse plantar skin showed prominent expression of C5aR1 in macrophages. Additionally, C5a evoked strong Ca2+ mobilization in macrophages. Macrophage depletion in transgenic macrophage Fas-induced apoptosis (MAFIA) mice abolished C5a-dependent thermal and mechanical hyperalgesia. Examination of inflammatory mediators following C5a injection revealed a rapid upregulation of nerve growth factor (NGF), a mediator known to sensitize TRPV1. Pre-injection of an NGF-neutralizing antibody or Trk inhibitor GNF-5837 prevented C5a-induced thermal hyperalgesia. Notably, NGF-induced thermal hyperalgesia was unaffected by macrophage depletion. Collectively, these results suggest that C5a induces thermal and mechanical hyperalgesia by triggering macrophage-dependent signaling that involves mobilization of NGF and NGF-dependent sensitization of TRPV1. Our findings highlight the importance of macrophage-to-neuron signaling in pain processing and identify C5a, NGF and TRPV1 as key players in this cross-cellular communication.

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7

Mickle, Aaron David. "Pain sensitization by parathyroid hormone-related peptide via convergent phosphoregulation of TRPV1". Diss., University of Iowa, 2014. https://ir.uiowa.edu/etd/5970.

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The neurobiological mechanisms underlying chronic pain in bone-metastasized breast and prostate cancer are not well understood although it is hypothesized that factors released in the tumor microenvironment may modulate sensory nociceptive sensory nerve fibers innervating the bone increasing pain sensation. Advanced metastatic breast and prostate cancer cells secrete high levels of parathyroid hormone-related peptide (PTHrP), which plays a critical role in metastasis to bones and subsequent tumor growth. PTHrP can activate parathyroid hormone receptor 1 (PTH1R), which signaling can activate either protein kinase C (PKC) and/or protein kinase A (PKA) depending on the tissue type. Both of these kinases are well known to modulate the nociceptive ion channel transient receptor potential vanilloid member 1 (TRPV1) due to which PTHrP constitutes an intriguing candidate that could modulate nociceptors, for pain sensitization related to cancer. TRPV1 can be activated by temperatures greater than 43°C and moderately acidic pH, less than pH 6. However, PKC and PKA phosphorylation of TRPV1 can potentiation channel activity by reducing the temperature of activation to 37°C and proton activation to pH 6.8 resulting in a channel that is constitutively active at body temperature or in the mildly acidic tumor microenvironment. Additionally, Src kinase, which under certain circumstances can be activated by PKC, can increase trafficking of TRPV1 to the plasma membrane, and enhance TRPV1-mediated signaling. Therefore, I hypothesize that PTHrP can sensitize TRPV1 and lead to an increase in nociceptive signaling. First I show that intraplantar PTHrP injection causes a TRPV1-dependent increase in thermal and mechanical hypersensitivity in mice. PTHrP treatment of cultured mouse dorsal root ganglion (DRG) neurons enhances TRPV1 activation and increases action potential firing, which was dependent on PKC activation. Furthermore, co-injection of PKC inhibitor attenuated PTHrP-induced thermal hypersensitivity. I also observed that PTHrP activated Src which led to an increase in the number of TRPV1-responsive neurons and an increase in TRPV1 protein level in the plasma membrane. While investigating the role of PTHrP-induced Src phosphorylation of TRPV1 I made a startling observation. Inhibition of Src phosphorylation of TRPV1 completely abolished PKC-induced potentiation of TRPV1. I found that Src phosphorylation of TRPV1 regulated PKC-induced potentiation of channel activity elicited by bradykinin, nerve growth factor and PMA. However, it did not regulate PKA induced potentiation of TRPV1 channel activity. In summary, my results suggest that PTHrP in the tumor microenvironment could induce constitutive pathological sensitization of adjacent nociceptive sensory fibers via upregulation of TRPV1 function, trafficking and expression. These actions are dependent on Src and PKC phosphorylation of TRPV1. Additionally, I found that Src regulates PKC-induced phosphorylation of TRPV1 by PTHrP as well as other inflammatory mediators, suggesting a crucial role for Src in PKC-induced sensitization of TRPV1.

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8

Öjstedt, Erik, e Simon Pankalla. "Clinical Assessment of Disturbed Central Pain Modulation in Orofacial Pain". Thesis, Malmö universitet, Odontologiska fakulteten (OD), 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:mau:diva-19798.

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Syfte. Studiens syfte var att retrospektivt undersöka vilka kliniska variabler, bedömda under specialistundersökning av orofacial smärta, som kan förutsäga närvaro av en störd central smärtmodulering (DCPM). Material och metod. DC/TMD-data hämtades ur patientjournaler från 86 patienter som undersökts på Orofaciala smärtenheten på Malmö Universitet under perioden september 2012 till och med december 2013. Undersökta variabler omfattade smärtintensitet, smärtutbredning, smärtrelaterad nedsatthet, psykosociala variabler, refererad smärta samt kliniska fynd under somatosensoriska undersökningar. Baserat på denna data delades patienterna upp i en DCPM-grupp och en grupp utan DCPM. Allodyni, hyperalgesi, dysestesi, wind-up, regional/generell smärtutbredning samt eftersensation ansågs vara markörer för DCPM. Icke-parametriska statistiska analyser användes och en sannolikhetsnivå på P<0,05 ansågs vara signifikant. Resultat. Graden av ospecifika fysiska symptom och antalet refererande smärtor var signifikant högre i DCPM-gruppen. Den multivariata logistiska regressionen visade att ospecifika fysiska symptom, stress, smärtduration, smärtintensitet, smärtrelaterad nedsatthet, antalet refererande smärtpunkter, maximal gapning med och utan smärta, ångest samt antalet smärtinducerande käkrörelser var signifikanta marörer för DCPM (LR Chi2 = 26.89, p = 0.003, Pseudo R2 = 0.29). Slutsats. Denna studie indikerar att stress, ångest, smärtduration, smärtintensitet, smärtrelaterad nedsatthet, antalet refererande smärtpunkter, maximal gapning med och utan smärta samt antalet smärtinducerande käkrörelser är associerat med DCPM hos patienter med orofacial smärta.
Objective. To retrospectively investigate clinical variables that can predict the presence of disturbed central pain modulation (DCPM). Material and methods Medical records of 86 patients examined at the Orofacial Pain Unit at Malmö University from September 2012 to December 2013 were examined regarding pain intensity, pain distribution, pain-related disability, psychosocial variables, referred pain as well as somatosensory changes. Based on these variables, the patients were divided into a disturbed central pain modulation (DCPM) group and a non-DCPM group. Allodynia, hyperalgesia, dysesthesia, increased wind-up, regional/general pain distribution and aftersensation were considered as markers for DCPM. Non-parametric statistics were used and a probability level of P<0.05 was considered as significant. Results. The degree of unspecific physical symptoms and the number of sites eliciting pain referral were significantly higher in the DCPM group. In the multivariate regression model, the independent variables physical symptoms, stress, pain duration, characteristic pain intensity, pain-related disability, number of sites with referred pain, maximum mouth opening with and without pain, anxiety, and number of pain eliciting jaw movements significantly predicted DCPM (LR Chi2 = 26.89, p = 0.003, Pseudo R2 = 0.29). Conclusion. This study indicates that stress, anxiety, orofacial pain and its consequences, unspecific physical symptoms and jaw dysfunction are clinical signs of DCPM in patients with orofacial pain. Also, high number of palpations sites with referred pain over the masseter and temporal muscles and the TMJ indicate presence of DCPM.

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9

King, Jacqlyn. "Sensorimotor Abnormalities in Chronic Subacromial Pain: The Influence of Sex, Contribution of Pain, and Utility of Using the Contralateral Limb as a Control". Thesis, University of Oregon, 2018. http://hdl.handle.net/1794/23190.

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Patients with subacromial pain syndrome (SPS) display a number of sensorimotor deficits including alterations in pain processing, poor proprioception, and weakness at the symptomatic limb. The primary purpose of this dissertation was to explore whether the aforementioned deficits: (1) can be quantified by using the non-involved limb as a measure of control, (2) are purely localized to the symptomatic limb or represent a more generalized deficit, (3) are influenced by the presence of subacromial pain, and (4) present similarly in male and female patients. Here, we utilized modern clinical techniques in both a patient cohort with SPS and uninjured control cohort to address these aims. The results of this dissertation are applicable towards treatment of SPS as well as scientific understanding of sex on sensorimotor behavior.

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Bettini, Elizabeth, e Elizabeth Bettini. "Central Sensitization and Associated Factors in Adolescents With Joint Hypermobility and Dysautonomia". Diss., The University of Arizona, 2016. http://hdl.handle.net/10150/622947.

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Background: Postural Orthostatic Tachycardia Syndrome (POTS) is a disorder of the autonomic nervous system that has high association with chronic pain syndromes such as fibromyalgia, migraine disorders, and chronic abdominal pain in adolescents with the diagnosis. Many of these disorders are characterized as central sensitization disorders, or pathological pain memory mediated by neural plasticity. Ehlers Danlos Syndrome Type 3 (EDS-3), also called joint hypermobility syndrome (JHS) is a genetic disorder of the connective tissue that causes joint laxity and is also highly associated with chronic pain syndromes as well as POTS. Methods: This study proposed to characterize POTS as a disorder of central sensitization. The hypothesis, presented within the proposed theoretical model, demonstrates that JHS leads to chronic pain that results in central sensitization and autonomic nervous system dysfunction (POTS). Other factors that were evaluated were anxiety and function. A sample size of 40 adolescents between the ages of 12 and 19 years were recruited from the cardiology and pain clinics at Children’s National Medical Center. Analysis of data utilizing Wilcoxon, Chi square, Pearson correlation, and logistic regression tests were completed using SAS 9.3. Results: In comparison to those without POTS, there were no significant associations found between having the diagnosis of POTS and any other variable studied in the model. JHS had a stronger correlation with anxiety, central sensitization, both subjectively, and objectively with hyperalgesia on Aδ sensory nerve fiber when compared to those without JHS. Subjective central sensitization was highly correlated with anxiety, function, age, and female gender. Function and central sensitization had a significant association even when removing anxiety as a covariate. Conclusions: These findings suggest that joint hypermobility may be a factor that contributes to the development of central sensitization in individuals with chronic pain. Dysautonomia is likely not a disorder of central sensitization, but rather a variable related to joint hypermobility and chronic pain in ways yet to be discovered. As previously discussed in other literature, anxiety has strong associations with central sensitization and functional disability in chronic pain syndromes, and when treated effectively may increase function in those that suffer with these disorders.

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11

Lascelles, B. Duncan X. "Studies on the development of sensitization to acute surgical pain in the rat and dog". Thesis, University of Bristol, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296598.

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12

Lemming, Dag. "Experimental Aspects on Chronic Whiplash-Associated Pain". Doctoral thesis, Linköpings universitet, Rehabiliteringsmedicin, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-10693.

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Introduction: Chronic pain after whiplash trauma (chronic WAD) to the neck is still a common clinical problem in terms of pain management, rehabilitation and insurance claims. In contrast to the increased knowledge concerning mechanisms of chronic pain in general, no clinical guidelines exist concerning assessment, pain control and rehabilitation of patients with chronic WAD. Aim: The general aim of this thesis was to use experimental techniques to better understand the complex mechanisms underlying chronic pain after whiplash trauma. The specific aims of papers I and II were mainly to use analgesic drugs with different target mechanisms alone or in combinations to assess their effects on pain intensity (VAS). Experimental pain techniques were used in all studies to assess deep tissue sensitivity (electrical, mechanical and chemical stimuli). Paper IV aimed at assessing deep tissue sensitivity to mechanical and chemical stimulation. The aim in paper III was to investigate if biochemical changes in interstitial muscle tissue (trapezius muscle) could be detected in WAD patients. Materials and Methods: The thesis is based on three different groups of patients with chronic WAD. In paper III and IV two different groups of healthy controls also participated. All patients were initially assessed in the pain and rehabilitation centre. In paper I (30 patients) and II (20 patients) two different techniques of drug challenges were used. In paper I: morphine, ketamine and lidocaine were used as single drugs. In paper II: remifentanil, ketamine and placebo were used in combinations and together with experimental pain assessments. Microdialysis technique was used in paper III (22 patients from study IV and 20 controls). In paper IV (25 patients and 10 controls) a new quantitative method, computerized cuff pressure algometry, was used in combination with intramuscular saline. In all papers, experimental pain techniques for deep tissue assessment (except cutaneous electrical stimulation in paper I) were used in different combinations: intramuscular hypertonic saline infusion, intramuscular electrical stimulation and pressure algometry. Results and Conclusion: There are multiple mechanisms behind chronic whiplash-associated pain, opioid sensitive neurons, NMDA-receptors and even sodium channels might play a part. A significant share of the patients were pharmacological non-responders to analgesic drugs targeting the main afferent mechanisms involved in pain transmission, this implies activation of different pain processing mechanisms (i.e. enhanced facilitation or changes in the cortical and subcortical neuromatrix). Experimental pain assessments and drug challenges together indicate a state of central hyperexcitability. Ongoing peripheral nociception (paper III), central sensitization and dysregulation of pain from higher levels in the nervous system may interact. These findings are likely to be present early after a trauma, however it is not possible to say whether they are trauma-induced or actually represents pre-morbid variations. Clinical trials with early assessments of the somatosensory system (i.e., using experimental pain) and re-evaluations, early intervention (i.e. rehabilitation) and intensified pain management could give further knowledge.

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Dickinson, Annelise K. "Do you really want to hurt me? ostracism-induced physical pain sensitization in real-life relationships /". Diss., Connect to the thesis, 2009. http://hdl.handle.net/10066/3592.

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14

Ferguson, Adam Richard. "Neuropathic pain and the inhibition of learning within the spinal cord". Diss., Texas A&M University, 2004. http://hdl.handle.net/1969.1/350.

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Prior work from our laboratory has shown that the spinal cord is capable of supporting a simple form of instrumental (response-outcome) learning. In a typical experiment, animals are given a spinal transection at the second thoracic vertebra, and tested 24 h after surgery. If animals are given shock when their leg is in a resting position (controllable shock), they quickly learn to maintain the leg in a flexed position, thereby minimizing shock exposure. Animals exposed to shock that is independent of leg position (uncontrollable shock) fail to learn. This learning deficit can be induced by as little as 6 minutes of shock to either limb or to the tail, and lasts for up to 48 h. The aim of this dissertation was to explore whether the deficit shares behavioral features and pharmacological mechanisms similar to those involved in the induction of neuropathic pain. Work within the pain literature has identified a spinal hyperexcitability that is induced by intense stimulation of pain fibers. This phenomenon, known as central sensitization, is characterized by an increase in tactile reactivity (allodynia) that can be induced by shock or peripheral inflammation. Pharmacological findings have revealed that central sensitization depends on the activation of the N-methyl-D-aspartate (NMDA) and group I metabotropic glutamate receptors (mGluRs). Experiment 1 showed that uncontrollable shock induces a tactile allodynia similar to that observed in central sensitization. Experiment 2 showed that peripheral inflammation caused by a subcutaneous injection of formalin generates a dose-dependent deficit. Experiment 3 indicated that the formalin-induced deficit was observed 24 h after delivery of the stimulus. Experiments 4-8 revealed that the NMDA and group I mGluRs are involved in the deficit. The NMDA receptor was found to be necessary (Experiment 4), but only sufficient to induce a deficit at neurotoxic doses (Experiment 5). Both of the group I mGluRs (subtypes, mGluR1 and mGluR5) were found to be necessary (Experiments 6 & 7). A general group I mGluR agonist summated with a subthreshold intensity of shock to produce a robust deficit (Experiment 8), suggesting shock and mGluR activation produce a deficit through a common mechanism.

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Loo, Lipin. "Modulation of TRPV1, nociceptor sensitization , and induction of thermal hyperalgesia by C-type natriuretic peptide". Diss., University of Iowa, 2013. https://ir.uiowa.edu/etd/2571.

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Rheumatoid arthritis (RA) is caused by aberrant attack of the joints by native inflammatory system. This can lead to joint destruction and pain that can be debilitating. Increased angiogenesis and innervation by nociceptive afferent fibers are characteristic features of RA joints, which in addition to the elevated levels of a wide variety of inflammatory mediators, are thought to play an important role in the pathogenesis of chronic inflammatory pain associated with RA. Interestingly, a recent report indicates that C–type natriuretic peptide (CNP) is increased in the blood serum of RA patients. Natriuretic peptides (NPs) control natriuresis and normalize changes in blood pressure. Many biological effects of NPs are mediated by guanylate cyclase (GC)–coupled NP receptors, NPR–A and NPR–B, whereas the third NP receptor, NPR–C, lacks the GC kinase domain and acts as the NP clearance receptor. In addition, NPR–C can couple to specific Gái–βã–mediated intracellular signaling cascades in numerous cell types. Recent studies suggest that NPs are also involved in the regulation of pain sensitivity, although the underlying mechanisms remain largely unknown. In Aim 1, I show that CNP acutely sensitized the excitation of mouse dorsal root ganglia (DRG) sensory neurons that is dependent on the transient receptor potential vanilloid–1 (TRPV1). CNP potentiated capsaicin– and proton–activated TRPV1 currents in cultured mouse DRG neurons and increased neuronal firing frequency, an effect that was absent in DRG neurons from TRPV1−/−mice. Further, CNP injection into mouse hind paw led to the development of thermal hyperalgesia, which was absent in TRPV1−/−mice. In Aim 2, I dissected the signaling mechanism underlying TRPV1 sensitization by CNP. My results show that all 3 functional NPRs are expressed in mouse DRG neurons; however NPR–A/B–cGMP signaling is not involved in CNP–mediated sensitization of TRPV1. Interestingly, I observed that sensitization of TRPV1 by CNP is dependent on protein kinase C (PKC) activity. Furthermore, I found that NPR–C is co–expressed in TRPV1–expressing mouse DRG neurons and can be co–immunoprecipitated with Gαi, but not with Gαq/11 or Gαs subunits. CNP treatment induced translocation of PKCå to the plasma membrane of these neurons, which was attenuated by pertussis toxin pre–treatment. Accordingly, CNP–induced sensitization of TRPV1 was attenuated by pre–treatment of DRG neurons with the specific inhibitors of Gβã, phospholipase–Cβ (PLCβ) or PKC, but not of protein kinase A (PKA), and by mutations at two PKC phosphorylation sites, S502 and S800, in the TRPV1 protein. Furthermore, the development of thermal hyperalgesia in CNP–injected hindpaw was attenuated by administration of specific inhibitors of Gβã or PKC. Thus, my work identifies the Gβã–PLCâ–PKC–dependent potentiation of TRPV1 as a novel signaling cascade recruited by CNP in mouse DRG neurons that can lead to enhanced nociceptor excitability and thermal hypersensitivity. Such signaling cascade could presumably constitute one of the mechanisms underlying chronic inflammatory joint pain associated with RA.

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Bou, Sader Nehme Sarah. "Cortical mechanisms of comorbidity between pain sensitization and attention-deficit/hyperactivity disorder (ADHD) in a mouse model". Electronic Thesis or Diss., Bordeaux, 2024. http://www.theses.fr/2024BORD0488.

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Le trouble du déficit de l'attention avec ou sans hyperactivité (TDAH) et la douleur chronique sont deux syndromes complexes d’origine multifactorielle. Des études confirment une comorbidité entre ces deux pathologies. Cependant, les mécanismes ne sont toujours pas élucidés. Une hyperactivité des neurones de l’ACC et une dérégulation de la voie ACC-insula postérieure (PI) ont été démontrées dans un modèle de souris TDAH. La neuroinflammation serait impliquée dans cette concomitance. Notre hypothèse suggère que la neuroinflammation déclencherait une amplification de l’activité neuronale dans l’ACC, sensibilisant ainsi les voies impliquées dans les symptômes du TDAH et la perception douloureuse. Ce travail de thèse vise donc à identifier les mécanismes inflammatoires à l’origine du TDAH et de la sensibilisation douloureuse qui lui est associée, avec un intérêt porté sur le rôle du récepteur purinergique P2X4 dans cette comorbidité.Afin de répondre à cette question, nous avons généré un modèle de souris TDAH par injection unilatérale et intracérébroventriculaire de 6-hydroxydopamine (6-OHDA), à P5. D’une part, des souris sauvages mâles et femelles âgées de deux mois ont été sacrifiées, leurs cerveaux ont été extraits et leurs ACC et PI ont été disséqués. Des tissus fixés ont été utilisés pour des études morphologiques tandis que des tissus frais ont été utilisés pour des études transcriptomique, protéomique et phosphoprotéomique. D’autre part, des souris avec un knock-out total du récepteur P2X4 ont été soumises à des tests de sensibilisation à la douleur (thermique et mécanique) et d'hyperactivité. Les tissus provenant d’ACC fixés ont été utilisés afin d’étudier les changements morphologiques microgliaux tandis que des tissus provenant d’ACC et de PI fraîchement extraits ont été utilisés pour des analyses transcriptomiques.En ce qui concerne les marqueurs identifiés chez les souris modèles de TDAH, nos résultats démontrent (i) des changements dans la morphologie des cellules microgliale et astrocytaire, associés à une réactivité cellulaire, dans l'ACC des souris 6-OHDA, (ii) la présence d’un environnement pro-inflammatoire dans l'ACC et la PI des souris 6-OHDA, (iii) des modifications dans l'expression de multiples protéines et l’activité de plusieurs kinases (sérine-thréonine et tyrosine) dans l'ACC et la PI des souris 6-OHDA, associées à des altérations du guidage axonal, de l’apoptose, de la dynamique du cytosquelette, de cascades de signalisation, de neurotrophines et de neurotransmetteurs, et (iv) des variations des interactions neurones-glie, et en particulier de la communication entre les neurones et les astrocytes dans l'ACC des souris 6-OHDA. L'intégration des données a permis d'identifier quatre processus altérés dans l'ACC et la PI des souris mâles et femelles 6-OHDA : l'apoptose, le guidage axonal, la plasticité synaptique (potentialisation à long terme) et la croissance des prolongements neuronaux ; des processus précédemment associés au TDAH et aux douleurs chroniques. De plus, nos résultats suggèrent un effet délétère du récepteur P2X4 sur l’activité locomotrice des souris et la réactivité microgliale. Il exercerait néanmoins un effet protecteur en limitant l'expression de molécules pro-inflammatoires, probablement sécrétées par des cellules non-microgliales.En conclusion, nos travaux fournissent des pistes sur les mécanismes inflammatoires qui sous-tendent la comorbidité entre le TDAH et la sensibilisation à la douleur. Ces pistes devront ultérieurement être validées individuellement. Le maintien d’un environnement pro-inflammatoire dans l'ACC et la PI entraîne des changements dans certains processus synaptiques (potentialisation à long-terme, guidage axonal, croissance des composants neuronaux) et apoptotiques. Ces altérations modifieraient la connectivité cellulaire et l'activité neuronale, participant ainsi à la pathogenèse du TDAH et de la douleur chronique
Attention deficit/hyperactivity disorder (ADHD) and chronic pain are two complex conditions of multifactorial origins. Clinical and preclinical studies support an association between these two syndromes. However, the mechanisms underlying their comorbidity are not well understood. Previous findings from our team demonstrated a hyperactivity of the neurons of the anterior cingulate cortex (ACC) and a deregulation of the ACC-posterior insula (PI) pathway in ADHD-like conditions. Growing evidence also suggests a role for neuroinflammation in this concomitance. Our hypothesis thus suggests that neuroinflammation triggers an enhanced neuronal activity in the ACC that sensitizes pathways involved in ADHD symptoms and pain perception. Therefore, this Ph.D. work aims to elucidate the inflammatory mechanisms that may underlie ADHD and its associated pain sensitization, with an interest in the role of the purinergic P2X4 receptor.To address this question, we generated an ADHD-like mouse model through the unilateral intracerebroventricular injection of 6-hydroxydopamine (6-OHDA) at P5. Two-month-old wild-type male and female mice were sacrificed, their brains were extracted, and their ACC and PI were dissected. Fixed tissues were used to study microglial and astrocytic morphology while fresh tissues were utilized for transcriptomic, proteomic, and phosphoproteomic investigations. Moreover, mice with a total knock-out of the P2X4 receptor were tested for thermal and mechanical pain sensitization, in addition to hyperactivity. Fixed tissues of the ACC were used to study changes in microglial morphology while fresh tissues of the ACC and PI were utilized for transcriptomic analyses.Regarding the identification of inflammatory mechanisms in our ADHD-like mouse model, our results report (i) changes in microglial and astrocytic morphology, associated with cellular reactivity, in the ACC of 6-OHDA mice, (ii) the presence of a pro-inflammatory environment in the ACC and PI of 6-OHDA mice, (iii) modifications in protein expression and kinase (serine-threonine and tyrosine) activity in the ACC and PI of 6-OHDA mice, and correlated with impairments in axon guidance, apoptosis, cytoskeleton dynamics, signaling cascades, neurotrophins, and neurotransmitter systems, and (iv) alterations in protein interactions and, therefore, neuronal-astrocytic communication in the ACC of 6-OHDA mice. Finally, data integration identified four processes impaired in the ACC and PI of 6-OHDA males and females: apoptosis, axon guidance, synaptic plasticity (long-term potentiation), and growth of neuronal components. Interestingly, alterations in these processes were not only linked to ADHD and chronic pain conditions but also associated with Eph/ephrin bidirectional signaling cascades. Our findings also indicate a role for the P2X4 receptor in the worsening of ADHD hyperactivity symptom and the induction of morphological changes in microglial cells that correlate with cellular reactivity. However, it exerts a protective effect by limiting the expression of pro-inflammatory molecules, possibly from non-microglial cells.In conclusion, our work provides interesting insights into the inflammatory mechanisms that may underpin the comorbidity between ADHD and pain sensitization. A mild and sustained pro-inflammatory environment in the ACC and PI drives changes in synaptic-related (long-term potentiation, axon guidance, outgrowth of neuronal components) and apoptotic processes. These impairments alter cell-cell connectivity and neuronal activity, thus participating in ADHD and chronic pain pathogenesis

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Yan, Jin, Ohannes Melemedjian, Theodore Price e Gregory Dussor. "Sensitization of dural afferents underlies migraine-related behavior following meningeal application of interleukin-6 (IL-6)". BioMed Central, 2012. http://hdl.handle.net/10150/610216.

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BACKGROUND:Migraine headache is one of the most common neurological disorders, but the pathophysiology contributing to migraine is poorly understood. Intracranial interleukin-6 (IL-6) levels have been shown to be elevated during migraine attacks, suggesting that this cytokine may facilitate pain signaling from the meninges and contribute to the development of headache.METHODS:Cutaneous allodynia was measured in rats following stimulation of the dura with IL-6 alone or in combination with the MEK inhibitor, U0126. The number of action potentials and latency to the first action potential peak in response to a ramp current stimulus as well as current threshold were measured in retrogradely-labeled dural afferents using patch-clamp electrophysiology. These recordings were performed in the presence of IL-6 alone or in combination with U0126. Association between ERK1 and Nav1.7 following IL-6 treatment was also measured by co-immunoprecipitation.RESULTS:Here we report that in awake animals, direct application of IL-6 to the dura produced dose-dependent facial and hindpaw allodynia. The MEK inhibitor U0126 blocked IL-6-induced allodynia indicating that IL-6 produced this behavioral effect through the MAP kinase pathway. In trigeminal neurons retrogradely labeled from the dura, IL-6 application decreased the current threshold for action potential firing. In response to a ramp current stimulus, cells treated with IL-6 showed an increase in the numbers of action potentials and a decrease in latency to the first spike, an effect consistent with phosphorylation of the sodium channel Nav1.7. Pretreatment with U0126 reversed hyperexcitability following IL-6 treatment. Moreover, co-immunoprecipitation experiments demonstrated an increased association between ERK1 and Nav1.7 following IL-6 treatment.CONCLUSIONS:Our results indicate that IL-6 enhances the excitability of dural afferents likely via ERK-mediated modulation of Nav1.7 and these responses contribute to migraine-related pain behavior in vivo. These data provide a cellular mechanism by which IL-6 in the meninges causes sensitization of dural afferents therefore contributing to the pathogenesis of migraine headache.

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Schäfer, Axel. "Low back related leg pain: development and preliminary validation of a new classification system". Thesis, Curtin University, 2009. http://hdl.handle.net/20.500.11937/235.

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Background summary. Leg pain is a common complaint in relation to low back pain (LBP), present in up to 65% of all patients with LBP. Radiating leg pain is an important predictor for chronicity of LBP and an indicator of the severity of the disorder. Consequently patients with back and leg pain account for a disproportionate amount of the costs of medical care and disability compensation caused by LBP. As many structures in the lower quarter are capable of evoking a similar pattern of pain, the primary pathology causing low back related leg pain is often difficult to differentiate resulting in inappropriate investigations and treatment.A number of published classification systems for LBP based on symptom response and pathoanatomy incorporate radiating leg pain. While these systems may be suitable and successful for LBP, this approach may be insufficient for the more complex pain conditions related to nerve injury. Failure to correctly classify subjects into homogenous subgroups could be one reason why randomized controlled trials often report conflicting results for conservative treatment of patients with sciatica. Mechanism based classification of patients is crucial in that it not only provides a better understanding of the presenting complaint, but also directs treatments which interact with specific neurophysiologic pain mechanisms. Therefore we developed a new classification system for low back related leg pain on the basis of pathomechanisms extending the ideas originally proposed by Elvey and Hall, with four distinct subgroups. These hierarchical categories are: Neuropathic Sensitization (NS) comprising major features of neuropathic pain with sensory sensitization; Denervation (D) arising from significant axonal compromise without major features of neuropathic pain; Peripheral Nerve Sensitization (PNS) arising from nerve trunk inflammation without clinical evidence of significant denervation; and Musculoskeletal (M) referred from non-neural structures such as the disc or facet joints.Objective. The objective of the research project was to investigate aspects of validity of the classification system: Inter-rater reliability, concurrent validity, and predictive validity.Methods. As there is no gold standard against which the classification system can be tested, three studies were undertaken to investigate inter-rater reliability, concurrent validity and predictive validity. Inter-rater reliability was tested consecutively by six blinded experienced clinicians in a subset of 40 patients. Concurrent validity was investigated by implementing a comprehensive quantitative sensory test (QST) protocol as a criterion measure within a cross-sectional cohort design. The aim was to explore whether sensory profiles of the different diagnostic groups would correlate with the putative pathomechanisms in each group. To investigate predictive validity we conducted a longitudinal cohort study to explore whether treatment response differs between diagnostic groups. Outcome measures were pain intensity, degree of disability and patient global perceived change as well as QST parameters related to small nerve fibre function and pain sensitivity.Results. Seventy-seven patients with unilateral low back related leg pain and 18 healthy age and sex matched controls were included. The proportion of patients in each classification were 26% in Group NS, 36% in Group D, 12% in Group PNS and 26% in Group M. Interrater reliability was good (percentage agreement = 80; κ = 0.72; 95% CI = 0.57 to 0.86). QST revealed signs of pain hypersensitivity in Group NS compared to a healthy control group. Significant sensory deficits occurred only in Group D and were most pronounced over the affected foot. QST parameters in Groups PNS and M were not significantly different to healthy controls. The longitudinal cohort study showed that the proportion of patients responding to treatment was greater in PNS (55.6%) than the other three groups (NS 10%; D 14.3 % and M 10%; Fishers exact test p=0.031). The mean magnitude of improvement was greater in Group PNS in all outcome measures compared to the other groups (p ≤ 0.052). Additionally, Group PNS showed a greater improvement pre to post treatment of C fibre function, decreased sensitivity to cold pain and decreasedtemporal summation compared to the other groups (all p<0.05). In contrast, GroupNS exhibited loss of C fibre function and increased pressure pain sensitivityfollowing treatment (all p<0.05).Discussion. Patients with low back related leg pain could be reliably classified into four groups by experienced musculoskeletal physiotherapists using a new classification system. Reliability is an essential requirement for any classification system to be valid. Significant differences in QST thresholds were found in groups NS and D when comparing them to a group of healthy controls, indicating that in these two groups sensory dysfunctions were most pronounced. These dysfunctions match findings from the clinical examination: Sensory deficits in Group D and pain hypersensitivity in Group NS. These findings support concurrent validity. The findings of the longitudinal study indicate that the new classification system identifies a subgroup of patients (PNS) more likely to respond to neural mobilisation intervention. This result contributes to the evidence for predictive validity of the classification system and supports the concept that correct categorization of subjects will improve treatment outcomes.Conclusion. The findings of our research project support validity of the new classification system and its use as a reliable and feasible tool to improve diagnosis and treatment outcome in patients with low back related leg pain.

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Bräscher, Anne-Kathrin [Verfasser], e Rupert [Akademischer Betreuer] Hölzl. "Cognitive and Behavioral Context of Pain Facilitation: Nocebo Conditioning and Uncontrollability-Induced Sensitization / Anne-Kathrin Bräscher. Betreuer: Rupert Hölzl". Mannheim : Universitätsbibliothek Mannheim, 2014. http://d-nb.info/1053618700/34.

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Shang, Ye. "Mechanisms Regulating Transient Receptor Potential Cation Channel A1 (TRPA1) and Their Roles in Nociception and Nociceptive Sensitization". eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1092.

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Nociception is the sensory nervous system that detects harmful stimuli including excessive heat, cold, toxic chemicals, and noxious mechanical stimulations. Transient receptor potential (TRP) channels are a group of evolutionarily conserved ion channels consisting of 4 subunits, each with 6 transmembrane spans, and detect a variety of external and internal nociceptive stimuli. Due to their critical roles in nociception, it is essential to understand the mechanisms that regulate TRP channels and subsequent nociception. Here, I investigated two distinct types of regulation of Drosophila transient receptor potential cation channel A1 (TrpA1): regulation via the expression of different TrpA1 isoforms, and via its binding with associated proteins. I found that one of the TrpA1 isoforms, TrpA1(E), inhibits the thermal responses of other TrpA1 isoforms in vitro. I also identified potential TrpA1 binding partners through Co- immunoprecipitation (Co-IP) and mass spectrometry analysis. These binding partners need further validation and characterization through biochemical, cellular, and behavioral assays to illustrate their roles in nociception, and may serve as potential drug targets for chronic pain.

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Lepri, Beatrice. "Efficacia della Pain Neuroscience Education in pazienti con dolore cronico da sensibilizzazione centrale: una revisione sistematica della letteratura". Bachelor's thesis, Alma Mater Studiorum - Università di Bologna, 2021. http://amslaurea.unibo.it/24579/.

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Background: Il dolore muscoloscheletrico (MSK) cronico influisce in termini di disabilità, qualità di vita e costi di gestione a livello mondiale; è conseguenza di più fattori (biologici, psicologici e sociali), infatti per gestirlo è fondamentale un approccio multidisciplinare (farmacologico, riabilitativo e psico-educativo). In questo scenario, la PNE (Pain Neuroscience Education) è una tecnica educativa mirata a “riconcettualizzare” il dolore, spiegandone i meccanismi di base ai pazienti, è molto usata per quelli con dolore cronico da sensibilizzazione centrale. Obiettivi: valutare l’efficacia della PNE su dolore, disabilità, fattori psicosociali; in pazienti con dolore MSK cronico da sensibilizzazione centrale - attraverso una revisione sistematica di RCTs. Materiali e metodi: La ricerca è stata condotta su tre banche dati: PubMed, PEDro, CINAHL. Sono stati inclusi RCTs che avessero adottato criteri di inclusione specifici per la sensibilizzazione centrale o che avessero individuato condizioni cliniche, strumenti o fattori psicosociali che la letteratura ha dimostrato essere correlati a dominanza da sensibilizzazione centrale (CSI, TSK, FABQ, PCQ, PSEQ, PCS). Qualità metodologica e rischio di bias sono stati valutati con Rob1 e PEDro scale. Risultati: sono stati inclusi quindici RCTs, la maggior parte di questi presentava un basso rischio di bias, eccetto il performance bias.. I risultati sono stati analizzati solo qualitativamente, in base ai criteri diagnostici dei pazienti inclusi (fibromialgia, lombalgia cronica, sindrome da fatica cronica, dolore spinale cronico, lombalgia e/o fibromialgia) rapportati agli outcome d’interesse (dolore, disabilità, fattori psicosociali). Conclusioni: La PNE sembra efficace nel migliorare gli outcome indagati, soprattutto se combinata ad altri interventi, in pazienti con fibromialgia e lombalgia cronica; mentre nel breve termine sembra efficace anche sola, in pazienti con dolore spinale cronico o sindrome da fatica cronica.

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Carcolé, Estrada Mireia 1988. "Role of the sigma-1 receptor in the pathophysiology of osteoarthritis pain". Doctoral thesis, Universitat Pompeu Fabra, 2019. http://hdl.handle.net/10803/668154.

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Osteoarthritis is the most common musculoskeletal disease worldwide, characterized by degradation of the articular cartilage, chronic joint pain and disability. Currently available treatments for osteoarthritis have limited efficacy and significant side effects. Understanding the neurobiological mechanisms involved in the development and maintenance of this chronic pain condition and the pain-related comorbidities is crucial to develop novel therapeutic alternatives. The present thesis is focused on the role of the sigma-1 receptor (σ1R), a chaperone expressed in key areas for pain control, modulating chronic osteoarthritis pain and opioid analgesic tolerance. Using a mouse model of osteoarthritis pain, we demonstrated that the pharmacological blockade of the σ1R produces acute and long-lasting effects inhibiting osteoarthritis pain and its cognitive and emotional manifestations. Moreover, the σ1R antagonist restored morphine-induced antinociception in opioid-tolerant individuals, constituting a potential therapeutic strategy for the multimodal management of chronic pain. We found that the σ1R antagonist modulates a neurobiological pathway common to osteoarthritis pain and opioid tolerance, involving µ-opioid receptor activity, neuroinflammation and glutamatergic signalling. The relevance of this pathway is highlighted through the identification of a promising treatment, based on simultaneous blockade of σ1R and stimulation of the µ-opioid receptor, which relieves osteoarthritis pain without inducing tolerance. Overall we combined behavioural, biochemical and electrophysiological approaches to advance in the understanding of the role of σ1R on osteoarthritis pain manifestations, and identified σ1R antagonists as efficient therapeutic agents to inhibit chronic osteoarthritis pain and the deleterious side effects of opioid prescription drugs.
La osteoartritis es la malaltia musculoesquelètica més comú arreu del món, caracteritzada per la degradació del cartílag articular, dolor crònic a les articulacions i discapacitat física. Els tractaments disponibles actualment per la osteoartritis tenen una eficàcia limitada i presenten efectes secundaris significatius. Comprendre els mecanismes neurobiologics implicats en el desenvolupament i el manteniment d’aquest tipus de dolor crònic i les comorbiditats associades és crucial per desenvolupar noves alternatives terapèutiques. La present tesis està centrada en el paper del receptor sigma-1 (σ1R), una xaperona expressada en àrees clau pel control del dolor, modulant el dolor osteoartrític i la tolerància a l’analgèsia opioide. Utilitzant un model de dolor osteoartrític en ratolí, hem demostrat que el bloqueig farmacològic del σ1R produeix efectes aguts i persistents inhibint el dolor osteoartrític i les seves manifestacions cognitives i emocionals. A més, l’antagonista del σ1R restaura l’antinocicepció induïda per la morfina en individus tolerants als opioides, essent llavors una estratègia terapèutica apropiada per el control multimodal del dolor crònic. Hem observat que l’antagonista del σ1R modula una via neurobiològica comú a la osteoartritis i a la tolerància opioide, la qual implica l’activitat del receptor opioide µ, mediadors neuroinflamatoris i senyalització glutamatèrgica. La rellevància d’aquesta via queda emfatitzada per la identificació d’un prometedor tractament, basat en el bloqueig del σ1R i la simultània estimulació del receptor opioide µ, que alleugereix el dolor osteoartrític sense induir tolerància. En general, hem combinat tècniques comportamentals, bioquímiques i electrofisiológiques per avançar en la comprensió del paper del σ1R en diferents manifestacions de la osteoartritis, i hem identificat els antagonistes σ1R com agents terapèutics eficients per inhibir el dolor osteoartrític crònic i els efectes secundaris perjudicials dels medicaments opioides.

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Custodio, Lilian. "SPINAL KAPPA OPIOID RECEPTOR ACTIVITY INHIBITS ADENYLYL CYCLASE-1 DEPENDENT MECHANISMS OF CHRONIC POSTOPERATIVE PAIN". UKnowledge, 2019. https://uknowledge.uky.edu/physiology_etds/42.

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Chronic postoperative pain impacts millions of individuals worldwide that undergo a variety of surgical procedures. Opioids remain the mainstay analgesics of acute and perioperative pain; however, prolonged opioid therapy may lead to life-threating adverse effects, tolerance, dependence, and addiction. Therefore, unraveling the cellular mechanisms that drive persistent pain states and opposing endogenous analgesia provided by opioid receptor signaling, may lead to novel analgesics. Evidence suggests that tissue injury leads to increased sensitization of the spinal cord nociceptive neurons which increases susceptibility to chronic pain via an N-methyl-D-aspartate (NMDA) receptor activation of calcium-sensitive adenylyl cyclase isoform 1 (AC1). This phenomenon, named latent pain sensitization (LS), is mediated by a compensatory response of endogenous inhibitory systems. In this dissertation, we test the hypothesis that surgical insult promotes prolonged activation of kappa opioid receptors (KOR) which mask LS via attenuation of pro-nociceptive AC1 signaling pathways in both male and female animals. We employed a murine model of chronic postoperative pain that promotes LS in the spinal cord and closely resembles the phenotypic features of postoperative pain in human subjects. When behavioral signs of hyperalgesia resolved, we targeted spinal opioid receptor systems and pronociceptive modulators with intrathecal delivery of selective pharmacological antagonists and assessed behavioral signs of hyperalgesia and spinal nociceptive sensitization. We propose that LS is kept in remission by a long-lasting compensatory response of tonic endogenous KOR signaling that hinders a pronociceptive LS pathway that includes not only AC1 but also two downstream targets: protein kinase A (PKA) and exchange protein activated by cAMP (Epac1/2) - in a sex-dependent manner. Our results propose new therapeutic targets for the management of persistent postoperative pain and underscore the importance of tailoring sex-specific pain management strategies.

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Neto, João Pedro Oliveira dos Santos. "Alterações no processamento central e na função dos sistemas inibitórios descendentes em utentes com Dor Lombar Crónica". Master's thesis, Instituto Politécnico de Setúbal. Escola Superior de Saúde, 2018. http://hdl.handle.net/10400.26/25494.

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Relatório do Projeto de Investigação apresentado para cumprimento dos requisitos necessários à obtenção do grau de Mestre em Fisioterapia, área de especialização em Fisioterapia em Condições Músculo-Esqueléticas
Introdução: A Dor Lombar Crónica (DLC) é a condição músculo-esquelética mais prevalente da população portuguesa. Tendo em conta a sua natureza multidimensional, a evidência sugere que o critério tempo (mais de 12 semanas de duração) não caracteriza adequadamente os utentes com DLC, sendo importante avaliar os mecanismos de produção de dor subjacentes. Objetivo: Investigar a presença de alterações no funcionamento do Sistema Nervoso Central compatíveis com um estado de sensitização central (alterações no processamento central e na função dos sistemas inibitórios descendentes) em utentes com DLC. Metodologia: Realizou-se um estudo observacional analítico do tipo caso-controlo, com base numa amostra constituída por 13 utentes com DLC e 13 indivíduos assintomáticos com características semelhantes de idade e género, que cumpriram os critérios de inclusão estabelecidos. Foram avaliados os limiares de dor à pressão (LDP) na coluna lombar, dorso do pé homolateral e região tenar da mão contralateral no sentido de avaliar a presença de sinais de alterações no processamento central. Com o intuito de avaliar a função dos sistemas inibitórios descendentes foram utilizados os testes Modulação Condicionada da Dor (MCD) e Adaptabilidade à dor. Resultados: Não se verificaram diferenças estatisticamente significativas entre grupos no LDP, no limiar de tolerância à dor à pressão (estímulo de teste do protocolo MCD) e na adaptabilidade à dor (p>0,05). Contudo, os resultados demonstram uma tendência para pontuações médias inferiores no LDP na coluna lombar nos indivíduos com DLC. Os resultados revelam também uma tendência para pontuações médias inferiores no limiar de tolerância à dor à pressão (LTDP – estímulo de teste no protocolo de MCD) imediatamente após o término da aplicação do estímulo de condicionamento e na adaptabilidade à dor nos indivíduos com DLC. Indivíduos com DLC de origem predominantemente neuropática demonstraram uma tendência para pontuações médias inferiores no LDP em todos os locais de aplicação, bem como no LTDP em todos os momentos de avaliação definidos no protocolo de MCD e na adaptabilidade à dor. Conclusões: Embora sem diferenças estatisticamente significativas entre os grupos, os resultados demonstram uma tendência para alterações no processamento central e função dos sistemas inibitórios descendentes nos indivíduos com DLC de características predominantemente neuropáticas, sugestivas de sensitização central e com elevado impacto funcional e psicossocial. Estes resultados sugerem a necessidade de investigar diferenças entre sub-grupos de utentes com DLC (dor nociceptiva/ neuropática) e as suas implicações em contexto clínico e de investigação.
Introduction: Chronic Low Back Pain (CLBP) is the most prevalent musculoskeletal condition in the Portuguese population. Given its multidimensional nature, the evidence suggests that the time criterion (over 12 weeks duration) does not adequately characterize CLBP patients, and it is important to evaluate the mechanisms underlying pain production. Objetive: To investigate the presence of alterations in the functioning of the Central Nervous System compatible with a central sensitization state (changes in central processing and the function of the descending inhibitory systems) in patients with CLBP. Methodology: An observational, case-control, observational study was performed based on a sample of 13 patients with CLBP and 13 asymptomatic individuals with similar characteristics of age and gender, who met the established inclusion criteria. Pressure pain thresholds (PPT) were evaluated in the lumbar spine, back of the homolateral foot and the tenar region of the contralateral hand in order to evaluate the presence of signs of changes in central processing. In order to evaluate the function of the descending inhibitory systems, the Conditioned Pain Modulation (CPM) and Pain Adaptability tests were used. Results: There were no statistically significant differences between groups in PPT, in pressure pain tolerance threshold to pressure (PPTT - test stimulus in the CPM protocol) and pain adaptability (p> 0.05). However, the results demonstrate a tendency for lower mean scores in PPT in the lumbar spine in subjects with CLBP. The results also reveal a tendency for lower mean scores in PPTT immediately after the end of the application of the conditioning stimulus and in pain adaptability in individuals with DLC. Individuals with predominantly neuropathic CLBP demonstrated a tendency for lower mean scores in PPT at all sites of application as well as in PPTT at all time points defined in the CPM protocol and in pain adaptability. Conclusions: Although there were no statistically significant differences between groups, the results showed a tendency for alterations in central processing and function of the descending inhibitory systems in individuals with CLBP of predominantly neuropathic characteristics, suggestive of central sensitization and with high functional and psychosocial impact. These results suggest the need to investigate differences between subgroups of patients with CLBP (nociceptive / neuropathic pain) and their implications in clinical and research context.

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Paz, Carolina Ribeiro Freitas da. "Clínica médica e cirúrgica em animais de companhia". Master's thesis, Universidade de Évora, 2016. http://hdl.handle.net/10174/19611.

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O presente relatório está inserido no âmbito da unidade curricular do Estágio Curricular do Mestrado Integrado em Medicina Veterinária da Universidade de Évora, sob orientação da Drª Sónia Lucena e coorientação da Drª Ângela Martins. Encontra-se dividido em duas partes, a primeira é referente à casuística acompanhada no Hospital Veterinário da Arrábida e Centro de Reabilitação Animal da Arrábida durante o período de cinco meses de estágio. Na casuística são expostos de forma breve os casos clínicos e procedimentos acompanhados durante o período de estágio. Na segunda parte é desenvolvida uma monografia intitulada “Maneio da dor crónica” acompanhada por uma descrição de um caso clínico assistido durante o estágio. A dor crónica é considerada uma dor patológica, deixando de ser um mecanismo de defesa do organismo e passando a ser considerada uma doença. É de difícil tratamento e requer um esforço multidisciplinar; ABSTRACT: Small Animal Medicine This report is conducted under the context of the curricular internship course unit of integrated master’s degree in Veterinary Medicine at the University of Évora under the supervision of Dr. Sónia Lucena and cosupervision of Dr. Ângela Martins. The first component refers to the assisted cases followed in Hospital Veterinário da Arrábida and Centro de Reabilitação Animal da Arrábida during the five months of the practice period. In the followed cases part it is explored briefly some clinical cases and procedures accompanied during that practice period. The second component consists of a monograph titled “Chronic pain management” accompanied with a description of a clinical case followed seen during the practice period. Chronic pain is considered a pathological pain, ceasing to be a defense mechanism of the body and to be considered a disease. It is difficult to treat and requires a multidisciplinary effort.

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Zanette, Simone de Azevedo. "Sistema modulador descendente da dor na fibromialgia : mediadores séricos e efeito da melatonina: ensaio clínico fase II, double-dummy, controlado". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2014. http://hdl.handle.net/10183/98468.

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Introdução: A fibromialgia (FM) é uma síndrome de dor crônica musculoesquelética difusa, cuja etiologia não está totalmente conhecida. A síndrome cursa com dor, alterações do humor e sintomas de ruptura do ritmo circadiano. Sabe-se que seu processo fisiopatogênico envolve um desbalanço entre os sistemas de modulação excitatório e inibitório da dor. A capacidade do sistema modulatório inibitório está enfraquecida, com hiperativação de neurônios e da neuroglia, constituindo um quadro de sensibilização central. Portanto, estudos adicionais são necessários para compreender a relação entre possíveis marcadores séricos da hiperativação neuronal, tais como o Brain Derived Neurotrophic Factor (BDNF) e a proteína S100 beta (S100B). Além disso, estudos que busquem opções terapêuticas com efeito em vias neurobiológicas alternativas, tais como a melatonina, uma indolamina com efeitos ressincronizador, analgésico, anti-inflamatório e em sistemas moduladores da dor, como o gabaérgico, opioidérgico e glutamatérgico. Objetivos: 1) Primário: Avaliar se os níveis séricos de BDNF e S100B teriam associação com a FM e se ambos os mediadores sorológicos poderiam ser associados com o limiar de dor à pressão. 2) Secundário: Testar o tratamento com melatonina isolada ou em combinação com amitriptilina é melhor que amitriptilina isolada para modificar o sistema modulatório da dor. Assim, para provar tais hipóteses, neste estudo foram quantificados a modulação condicionada da dor e níveis de BDNF sérico em pacientes que receberam tratamento com melatonina isolada ou associada com amitriptilina. Foi também testado se melatonina melhoraria os sintomas clínicos como dor, limiar de dor à pressão e qualidade do sono relacionado à FM. Métodos: Foram selecionadas pacientes com diagnóstico de FM de acordo com o American College of Rheumatology (ACR) 2010. No primeiro estudo, de desenho transversal, foram incluídas 56 mulheres com FM, com idades entre 18 e 65 anos. Foram avaliados o limiar de dor à pressão e dosagem sérica de BDNF e S100B. No segundo estudo, foram incluídas 63 pacientes com os mesmos critérios de inclusão descritos no estudo transversal. As pacientes foram randomizadas e receberam, ao deitar, amitriptilina (25mg) (n=21), melatonina (10mg) (n=21) ou melatonina (10 mg) + amitriptilina (25mg) (n=21), durante seis semanas. O sistema modulatório descendente da dor foi acessado pela modulação condicionada da dor, através da mensuração da escala numérica de dor (NPS(0-10)) durante aferição do limiar de dor ao calor. Resultados: O resultado do estudo transversal mostrou que BDNF e S100B séricos foram correlacionados. BDNF e S100B foram inversamente correlacionados com limiar de dor à pressão. BDNF sérico foi associado com limiar de dor à pressão, idade e transtorno obsessivo compulsivo, enquanto que S100B sérica foi apenas associada com limiar de dor à pressão. O ensaio clínico randomizado demonstrou que a melatonina aumentou a potência do sistema modulatório da dor inibitório e que a modulação condicionada da dor foi negativamente correlacionada com BDNF sérico. Conclusões: Os estudos desta tese demonstram que S100B e BDNF, ambos mediadores chave no processo de sensibilização central, foram inversamente correlacionados com o limiar de dor à pressão. BDNF sérico foi, ainda, inversamente correlacionado com a redução da dor. Portanto, a avaliação sérica de BDNF e S100B merece estudos adicionais para determinar seu potencial papel sinalizador no espectro da sensibilização central nessa doença.
Introduction: Fibromyalgia (FM) is a syndrome of chronic diffuse musculoskeletal pain whose etiology is not fully known. This syndrome causes pain, mood swings and symptoms of rupture of the circadian rhythm. Its pathophysiological process involves an imbalance between excitatory and inhibitory pain modulatory systems. The ability of inhibitory systems is weakened, providing a framework of central sensitization, with dysfunction in the descending pain modulatory system, hyper-activation of neurons and neuroglia. Therefore, additional studies are needed to understand the possible relationship between serum markers of neuronal hyperactivity, such as Brain Derived Neurotrophic Factor (BDNF) and S100B. Particularly, studies seeking therapeutic options with effect in neurobiological alternative pathways such as melatonin, a indolamine with resynchronization, analgesic, and anti-inflammatory effects and actions on the modulatory pain systems such as GABAergic, opiodergic and glutamatergic. Objectives: 1) Primary: Evaluate whether the serum levels of BDNF and S100B have association with FM and if both serological mediators could be associated with pressure pain threshold. 2) Secondary: To test the hypothesis that treatment with melatonin alone or in combination with amitriptyline is better than amitriptyline alone to modify the endogenous pain modulatory system. Thus, to prove these hypothesis, it was quantified the conditioned pain modulation and serum BDNF levels in FM patients receiving treatment with melatonin alone or in combination with amitriptyline. Also, it was tested whether melatonin would improve clinical symptoms such as pain, pressure pain threshold and quality of sleep related to FM. Methods: Patients with FM according to the American College of Rheumatology (ACR) 2010 were selected. In the first study, a cross-sectional design, 56 women aging 18-65 years old, with FM were included. It was evaluated the pressure pain threshold, and serum levels of BDNF and S100B. In the second study, 63 patients were included with the same inclusion criteria described in the cross-sectional study. Patients were randomized and received at bedtime amitriptyline (25 mg) (n = 21), melatonin (10 mg) (n = 21) or melatonin (10 mg) + amitriptyline (25 mg) (n = 21) for six weeks. The descending pain modulatory system was accessed by the conditioned pain modulation, measuring the numerical pain scale [NPS (0-10)] during the heat pain threshold. Results: On the cross-sectional study serum BDNF and S100B were correlated. Serum BDNF and S100B were correlated with the pressure pain threshold. Serum BDNF was associated with pressure pain threshold, age and obsessive compulsive disorder, while serum S100B was associated with pressure pain threshold, only. The randomized clinical trial showed that melatonin increased the efficacy of inhibitory pain modulatory system and the conditioned pain modulation was negatively correlated with serum BDNF. Conclusions: The studies of this thesis show that both key mediators of the central sensitization process, BDNF and S100B, were inversely correlated with the pressure pain threshold. They also showed that melatonin increased the inhibitory pain modutalory system. Furthermore, it emphasizes that serum BDNF was inversely correlated with pain reduction. Therefore, assessment of serum BDNF and S100B deserve further studies to determine their potential as a proxy for the central sensitization spectrum in FM.

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del, Pozo Blanco Olga. "Efectos sobre el dolor y la función de la terapia del espejo en el síndrome del túnel del carpo bilateral". Doctoral thesis, Universitat Rovira i Virgili, 2017. http://hdl.handle.net/10803/454720.

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La finalitat d'aquesta tesi és evaluar els efectes sobre el dolor i la funció que té la teràpia de l'espill al síndrom del túnel carpià bilateral, i a més, observar la relació entre el catastrofisme associat al dolor en la lesió, i els efectes de la tècnica. Un total de 18 pacients derivats del Servei de Traumatologia de l'Hospital de Manises de València (Espanya), participaren a l'assaig clínic, els quals van ser inclossos aleatòriament entre el grup espill i el placebo. Els pacients van emplenar qüestionaris per a avaluar el dolor, la funció i el catastrofisme associat al dolor. Durant les vuit setmanes que va durar la intervenció, entre el tractament efectuat amb l'investigador i el domiciliari, els subjectes del grup d'intervenció realitzaren exercicis amb un espill per a tindre feedback visual, mentres els del placebo els efectuaven amb l'espill girat. Una vegada realitzat l'anàlisi de les dades recopilades, es va observar que, els pacients inclosos al grup espill mostraven una reducció del dolor major que els que havien estat al placebo. Pel contrari, no es va evidenciar que la teràpia de l'espill tinguera repercussió sobre la funció. De la mateixa manera, el catastrofisme associat al dolor es va relacionar amb la intensitat percebuda del dolor, però no va ser determinant sobre els efectes de la tècnica estudiada. En conclusió, els resultats obtinguts ajuden a ampliar les estratègies de tractament habitualment emprades en rehabilitació, així como a aprofundir en el catastrofisme com a factor associat al dolor al síndrom del túnel carpià.
La finalidad de esta tesis es evaluar los efectos sobre el dolor y la función que tiene la terapia del espejo en el síndrome del túnel del carpo bilateral, y además observar la relación entre el catastrofismo asociado al dolor en la lesión, y en los efectos de la técnica. Un total de 18 pacientes derivados del Servicio de Traumatología del Hospital de Manises de Valencia (España), participaron en el ensayo clínico, los cuales fueron incluidos aleatoriamente entre el grupo espejo y el placebo. Los pacientes rellenaron cuestionarios para evaluar el dolor, la función, y el catastrofismo asociado al dolor. Durante las ocho semanas que duró la intervención, entre tratamiento efectuado con el investigador y el domiciliario, los sujetos del grupo de intervención realizaron ejercicios con un espejo para tener feedback visual, mientras los del placebo los efectuaban con el espejo girado. Una vez efectuado el análisis de los datos recopilados, se observó que, aquellos pacientes incluidos en el grupo espejo mostraron una reducción del dolor mayor que aquellos que se encontraban en el grupo placebo. Por el contrario, no se evidenció que la terapia del espejo tuviera repercusión sobre la función. Del mismo modo, el catastrofismo asociado al dolor se relacionó con la intensidad percibida del dolor, pero no fue determinante sobre los efectos de la técnica estudiada. En conclusión, los resultados obtenidos ayudan a ampliar las estrategias de tratamiento habitualmente empleadas en rehabilitación, así como a profundizar sobre el catastrofismo al ser un factor asociado al dolor en el síndrome del túnel del carpo.
The aim of this thesis is to evaluate the effects on pain and function of mirror therapy in bilateral Carpal Tunnel Syndrome, and also to observe the relationship between catastrophism associated with pain in the lesion and the effects of the technique. A total of 18 patients from the Trauma Service of the Manises Hospital of Valencia (Spain) participated in the clinical trial, which were randomly included between the mirror and placebo groups. Patients completed questionnaires to assess pain, function, and catastrophism associated with pain. During the eight weeks of the intervention, between investigator and home treatment, the subjects in the intervention group performed exercises with a mirror to have visual feedback, while those of the placebo performed with the mirror turned. After analyzing the collected datas, it was observed that those patients included in the mirror group showed a greater pain reduction than those who were in the placebo group. On the contrary, it was not evidenced that the mirror therapy had repercussion on the function. Similarly, catastrophism associated with pain was related to the perceived intensity of pain, but was not determinative of the effects of the technique studied. In conclusion, the results obtained help to broaden the treatment strategies commonly used in rehabilitation, as well as to deepen the catastrophism as a factor associated with pain in the carpal tunnel syndrome.

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Hazime, Fuad Ahmad. "Eficácia analgésica da estimulação elétrica cerebral e periférica na dor lombar crônica inespecífica: ensaio clínico aleatorizado, duplo-cego, fatorial". Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5170/tde-24022016-115652/.

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Recentes evidências sugerem que a dor lombar crônica está associada a alterações plásticas no cérebro, que podem ser modificadas por estratégias de neuromodulação. Neste ensaio clínico investigamos a eficácia analgésica de 12 sessões não consecutivas de estimulação transcraniana por corrente contínua (ETCC), estimulação elétrica periférica (EEP), ETCC+EEP e estimulação simulada (sham) em 92 pacientes com dor lombar crônica inespecífica. A intensidade, aspecto sensorial e afetivo da dor, incapacidade e percepção global de recuperação foram avaliadas antes do tratamento e quatro semanas, três e seis meses pós-randomização. Efeitos adversos, satisfação do paciente com o tratamento e fatores de confusão como ansiedade e depressão também foram avaliados. Os resultados demonstraram efeitos analgésicos clinicamente importantes da ETCC+EEP (MD = -2,6 IC95% = -4,4 a -0,9) e EEP isolada (MD = -2,2 IC95% = -3,9 a -0,4) comparada ao grupo sham, mas não da ETCC isolada (MD = -1,7 IC95% = -3,4 a -0,0). Além da manutenção do efeito analgésico por até três meses a ETCC+EEP obteve maior proporção de respondedores em diferentes pontos de corte. Os resultados sugerem que tanto a ETCC+EEP quanto EEP isolada são eficazes em curto prazo para o alívio da dor lombar crônica inespecífica. No entanto o efeito analgésico mais duradouro aliado a maior proporção de respondedores indicam um possível efeito aditivo e sinérgico da ETCC+EEP no alívio da dor em pacientes com dor lombar crônica não específica. Os nossos resultados não apoiam o uso da ETCC no regime de tratamento utilizado
Recent evidence suggests that chronic low back pain is associated with plastic changes in the brain that can be modified by neuromodulation strategies. In this clinical trial we have investigated the analgesic efficacy of 12 non-consecutive sessions of transcranial direct current stimulation (tDCS), peripheral electrical stimulation (PES), tDCS+PES and sham stimulation in 92 patients with chronic nonspecific low back pain. Intensity, the sensory and affective aspect of pain, disability, and overall perception of recovery were assessed before treatment and four weeks, three and six months post-randomization. Adverse effects, patient satisfaction with treatment and confounding factors such as anxiety and depression were also evaluated. The results showed clinically significant analgesic effects of tDCS+PES (Mean Reduction (MR) = -2.6; CI95% = -4.4 to - 0.9) and PES alone (MD = -2.2, CI95% = -3.9 to -0.4) compared to sham group, but not tDCS alone (MD = -1.7, CI95% = -3.4 to -0.0). In addition to maintaining the analgesic effect for up to three months, tDCS+PES treatment had a higher proportion of responders in different cutoff points. The results suggest that both tDCS+PES and PES alone are effective in relieving chronic nonspecific low back pain in the short term. However the most lasting analgesic effect, combined with a higher proportion of responders, indicates a possible additive and synergistic effect of tDCS+PES in relieving low back pain. Our findings do not support the use of tDCS alone in this condition

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Sydney, Priscila Brenner Hilgenberg. "Avaliação somatossensorial do sistema trigeminal em condições dolorosas crônicas: testes quantitativos sensoriais e limiar de percepção atual". Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/25/25135/tde-02092013-144216/.

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A dor crônica envolve complexos processos de gênese e condução neural e é decorrente da ativação de mecanismos periféricos e centrais de manutenção. Muitos pacientes crônicos são refratários aos diferentes tipos de tratamento propostos, o que gera a suspeita de que de alguma maneira estes não estão sendo totalmente eficazes. O objetivo deste trabalho é avaliar os mecanismos de condução, manutenção e modulação da dor em diferentes condições dolorosas crônicas. Foram avaliadas 92 mulheres, divididas em 5 grupos: Grupo I, 20 pacientes com Dor Miofascial da musculatura mastigatória; Grupo II, 20 pacientes com Fibromialgia; Grupo III, 20 pacientes com Cefaleia Crônica Diária; Grupo IV, 12 pacientes com Neuralgia Trigeminal e Grupo V, 20 pacientes saudáveis assintomáticas. Foram aplicados dois questionários, o IDATE e o OHIP-30, para mensuração do estado ansioso e da qualidade de vida relacionada a condição dolorosa diagnosticada, respectivamente. Todas as pacientes foram submetidas a Testes Quantitativos Sensoriais, como: Limiar de Dor à Pressão, Limiar de Detecção Mecânico, Limiar Doloroso Mecânico, Tolerância à Dor Isquêmica, Sensibilidade Dolorosa ao Frio, Sensação Pós-Estímulo e Controle da Modulação da Dor. Além disso, um Teste Eletrodiagnóstico, que determinou o Limiar de Percepção Atual, através do uso do aparelho Neurometer CPT/C (Neurotron®) foi realizado. Foram avaliadas 3 regiões em cada paciente: trigeminal, cervical e extratrigeminal. Os dados obtidos foram submetidos à análise estatística (ANOVA, Tukey, t-Student) adotando-se um nível de significância de 5% para todos os testes. Todos os grupos experimentais apresentaram altos níveis de ansiedade e grande comprometimento da sua qualidade de vida, quando comparados ao controle. Os Grupos I, II e III apresentaram valores de Limiar de Dor à Pressão significativamente menores do que o Grupo V. As mulheres do Grupo III apresentaram Limiar de Detecção Mecânico significativamente maior do que o Grupo V. Os Grupos I, II, III e IV apresentaram valores de Limiar de Doloroso Mecânico e Tolerância à Dor Isquêmica estatisticamente menores do que o Grupo V. A capacidade de ativação do mecanismo de modulação endógeno, avaliada pelo teste de Controle de Modulação da Dor, está comprometida nas mulheres com Dor Miofascial e Fibromialgia. Não houve diferença estatisticamente significante no Limiar de Percepção Atual (CPT) entre os Grupos I, II, III e V. Pacientes do Grupo IV apresentaram CPT para a frequência de 5Hz significativamente menor do que as do Grupo V na região trigeminal, indicando uma hiperestesia de origem inflamatória no nervo trigêmeo, caracterizando-se a dor neuropática. Ainda, de acordo com os resultados encontrados, os Grupos I, II e III parecem dividir um mecanismo de dor e etiologia semelhantes, não apresentando danos às estruturas neurais e sim uma alteração no processamento e modulação do impulso nociceptivo, caracterizando-se uma dor disfuncional. Os resultados deste estudo mostraram evidências da presença do processo de sensibilização central e prejuízo no mecanismo de modulação endógeno em pacientes com Dor Miofascial, Fibromialgia e Cefaleia Crônica Diária.
Chronic pain involves complex processes of genesis and neural conduction due to activation of peripheral and central mechanisms of pain maintenance. Many chronic patients are refractory to different types of treatment, which leads to the suspicion that somehow they are not fully effective and probably some mechanism of pain generation and/or maintenance is still unknown. Based on that, the aim of the present study is to evaluate the mechanisms of conduction, maintenance and pain modulation in patients with different types of chronic pain conditions. Ninety two women were evaluated, divided into 5 groups: Group I, 20 patients with Myofascial Pain of the masticatory muscles; Group II, 20 patients with Fibromyalgia; Group III, 20 patients with Chronic Daily Headache; Group IV, 12 patients with Trigeminal Neuralgia and Group V, 20 healthy asymptomatic patients. Two questionnaires were used, the STAI and the OHIP-30, to measure state anxiety and quality of life related to painful condition diagnosed, respectively. All patients underwent Quantitative Sensory Tests such as: Pressure Pain Threshold, Mechanical Detection Threshold, Mechanical Pain Threshold, Ischemic Pain Tolerance, Cold Pain Sensitivity, After- Sensation and Control Pain Modulation. An Electrodiagnostic Test, the Current Perception Threshold, using the apparatus Neurometer CPT/C (Neurotron®) was also performed. Three different regions were evaluated for each patient, for each test: trigeminal, cervical and extratrigeminal. Data were gathered and subjected to statistical analysis (ANOVA, Tukey, t-Student), adopting a significance level of 5% for all tests. All patients had high levels of anxiety and greater impairment of their quality of life, when compared to controls. Groups I, II and III showed significantly lower values of Pressure Pain Threshold than Group V. Group III had a significantly higher Mechanical Detection Threshold than Group V. Groups I, II, III and IV showed statistically lower values for Mechanical Pain Threshold and Ischemic Pain Tolerance than Group V. The ability to activate the mechanism of endogenous modulation, evaluated with the Controled Pain Modulation test, is impaired in women with Fibromyalgia and Myofascial Pain. There was no significant differences in the Current Perception Threshold (CPT) between Groups I, II, III and V. Group IV showed a CPT to 5 Hz frequency significantly lower than Group V for the trigeminal region, indicating an hyperesthesic condition due to inflammation of the trigeminal nerve, characterizing neuropathic pain. According to the results, Groups I, II and III seem to share a common pain mechanism and similar etiology, with no significant damage to neural structures but a change in the processing and modulation of nociceptive stimuli, characterizing a dysfunctional pain. The results of this study showed evidence of the presence of central sensitization process and impaired endogenous modulation system in patients with Myofascial Pain, Fibromyalgia and Chronic Daily Headache.

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Radwani, Houda. "Modulation de la transmission nociceptive par les récepteurs métabotropiques du glutamate de groupe I et les canaux calciques de type L dans la moelle épinière : approche électrophysiologique in vivo". Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0383/document.

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Abstract (sommario):

La douleur est une expérience désagréable qui fait partie de notre vie. Quand elle ne dure pas longtemps, elle est un signal d’alarme pour notre organisme. Cependant malheureusement, dans certaines conditions pathologiques, elle se prolonge dans le temps, elle devient alors chronique, intolérable, et nécessite un traitement qui ne suffit pas toujours à soulager le patient, un traitement qui dispose une efficacité limitée avec des effets secondaires indésirables non négligeables. Il est crucial alors d’améliorer nos connaissances sur les mécanismes enclenchés dans la transmission douloureuse pour développer des nouveaux outils thérapeutiques. Dans ce contexte, des études menées ces dernières années dans notre laboratoire ont indiqué que les neurones de la corne dorsale de la moelle épinière présentent des propriétés intrinsèques d’amplification des messages afférents douloureux qui reposent notamment sur des courants calciques via les canaux calciques de type L. Pour cela, le rôle de ces canaux L et plus particulièrement le rôle exact de chaque canal : Cav1.2 et Cav1.3, les deux seuls iso-formes des canaux L exprimés dans la corne dorsale de la moelle épinière, dans la sensibilisation douloureuse a été étudié dans la première partie de ce présent travail. Nous avons étudié chez le rat, in vivo, et en utilisant une approche computationnelle pour simuler l’activité neuronale, l’impact de ces courants Cav1.2 et Cav1.3, à la fois sur le phénomène de Wind-up, une forme de sensibilisation à court terme, et sur un modèle de neuropathie périphérie (SNL) caractérisé par une forme de sensibilisation à long terme. Nous avons pu montrer que la présence de Cav1.3 (mais pas de Cav1.2) est crucial pour l’expression du Wind-up quel que soit le contexte physiopathologique (contrôle/neuropathie), alors que la suppression de Cav1.2 (mais pas de Cav1.3) diminue significativement l’expression du comportement douloureux dans le contexte de neuropathie. D’autre part, il a été montré également dans notre laboratoire que les récepteurs métabotropiques de groupe I (mGluRs I), récepteurs du Glutamate, principal neurotransmetteur excitateur dans la transmission nociceptive, interagissent avec ces canaux L en modulant leur activité. Dans des conditions pathologiques telles que les conditions des douleurs inflammatoires le rôle de ces canaux L est controversé, et si l’interaction entre les mGluRs I et les canaux L est toujours présente dans ces conditions inflammatoires est mal connue. Nous avons décidé alors d’étudier dans la deuxième partie de ce travail le rôle de ces canaux L, et leur interaction avec les mGluRs I dans les conditions des douleurs inflammatoires. En utilisant des approches : l’électrophysiologie extracellulaire in vivo, pharmacologie, comportement, les injections intrathécales, et biologie moléculaire, nous avons montré que l’activation pharmacologique des mGluRs I augmente la transmission nociceptive et que cet effet nécessite l’activation des canaux calciques de type L dans les conditions contrôles. D'une façon inattendue, dans le contexte d’inflammation, nos résultats ont montré que l’activation des mGluRs I induit un effet totalement opposé anti-nociceptif et que cet effet est indépendant des canaux L. En plus, nous confirmons que le blocage des canaux L est sans effet dans le cas d’inflammation. D’autre part, nous avons montré que l’effet contradictoire dû à l’activation des mGluRs I passe par un renforcement de la transmission inhibitrice. En conclusion, nos résultats montrent l’intérêt de cibler les canaux calciques de type L et plus précisément le canal Cav1.2 dans le cadre des douleurs chroniques neuropathiques. De plus, nous montrons aussi que les mGluRs I pourraient être des bons candidats thérapeutiques dans le contexte inflammatoire
Pain is an unpleasant experience which is part of our lives. When it does not last long time, it is often a warning sign for our organism. However unfortunately, in some pathological cases, it can last a long time, and become chronic, intolerable, and requires a treatment that is not always enough to relieve the patient, a treatment that has limited efficacy with significant undesirable side effects. It is important now to ameliorate our knowledge about the mechanisms implicated in pain transmission to develop new therapeutic tools. In this context, many studies conducted in recent years in our laboratory have indicated that the neurons in the dorsal horn of the spinal cord express intrinsic amplification properties of afferents input rely on calcium currents via the L type calcium channels. For that, the role of L type calcium channels and especially the role exact of each canal: Cav1.2 and Cav1.3, the two only iso-forms of L channels expressed in the dorsal horn of the spinal cord, in the painful sensitization has been studied in the first part of this present work. We studied in rat, in vivo, and by using a computational approach to simulate neuronal activity, the impact of these currents Cav1.2 and Cav1.3, both on the phenomenon of Wind-up, a form of short term sensitization, and in the model of a peripheral neuropathy model (SNL) characterized by a form of long-term sensitization. We showed that the presence of Cav1.3 (but not the Cav1.2) is important for Wind-up’s expression regardless of the physio-pathological context (control / neuropathy), whereas the removal of Cav1.2 (but not Cav1.3) decreases significantly the expression of the pain behavior in the context of neuropathy. In another side, it has been shown in our laboratory that group I metabotropic glutamatergic receptors (mGluRs I), receptors of Glutamate, the main excitatory neurotransmitter in nociceptive transmission, interact with L channels by modulating their activity. In pathological condition such in the condition of inflammatory pain the role of these channels L is controversial, and if the interaction between mGluRs I and L channels is always present in these inflammatory conditions is poorly known. We decided then to study in the second part of this work the role of these channels, and their interaction with mGluRs I in the condition of inflammatory pain. By using electrophysiological extracellular recording, pharmacology, behavior, intrathecal injections, and molecular biology, we showed that pharmacological activation of mGluRs I increase the nociceptive transmission and that this effect requires the activation of L type calcium channels in control conditions. Unexpectedly, in the context of the inflammation, our results show that activation of mGluRs I induce an anti-nociceptive effect and this effect is independent of L channels. Moreover, we confirmed that the blockade of L calcium channels is without effect in case of the inflammation. Furthermore, we showed that the contradictory effect due to the activation of mGluRs I pass through a strengthening of inhibitory transmission. In conclusion, our results show the interest to target L type calcium channels and more specifically the Cav1.2 channel in case of neuropathic chronic pain. We also show that mGluRs I could be good therapeutic candidates in the inflammatory context

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31

Borella, Federica. "Tendon Neuroplastic Training, un nuovo approccio riabilitativo per la risoluzione del dolore e il ritorno allo sport nelle persone con tendinopatia achillea e patellare. Scoping review". Bachelor's thesis, Alma Mater Studiorum - Università di Bologna, 2020. http://amslaurea.unibo.it/21904/.

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Abstract (sommario):

Introduzione: le tendinopatie achillea e patellare sono le più frequenti a livello dell’arto inferiore e sono caratterizzate da sintomi persistenti quali dolore che si accentua col carico e compromissione della funzione. L’approccio riabilitativo tradizionale si basa su esercizi eccentrici isolati in carico, modalità che pare inefficace per circa il 45% dei pazienti. Stanno perciò emergendo nuove strategie riabilitative che includano altri tipi di contrazione muscolare. Si è ipotizzata una correlazione tra la persistenza dei sintomi e fenomeni di sensibilizzazione del SNC. Obiettivo: analizzare le nuove strategie basate sul carico nel trattamento della TA e TP - in particolare l’HSR – e le componenti di sensibilizzazione del SNC che sembrano ostacolare la riabilitazione. Materiali e metodi: consultazione delle principali banche dati. Si potevano includere studi primari e secondari. I soggetti dovevano presentare un quadro di TA o TP con eventuale associazione di alterazioni dell’elaborazione del dolore a livello centrale e dovevano essere sottoposti a un programma di esercizio eccentrico o ad HSR. Risultati: 5 studi hanno soddisfatto i criteri di inclusione. Tre studi confermano l’efficacia dell’HSR per il raggiungimento degli outcome desiderati, ma non in maniera statisticamente significativa rispetto all’esercizio eccentrico. Due articoli analizzavano se fosse presente un quadro di sensibilizzazione del SNC nei soggetti con TA e TP. Entrambi affermano la presenza di un’alterazione della capacità di modulazione centrale del dolore. Conclusioni: l’HSR risulta efficace per il trattamento della TA e TP in maniera sovrapponibile all’esercizio eccentrico tradizionale. L’alta percentuale di recidiva dei sintomi sembra causata da un’alterazione della capacità di modulare il dolore in questi pazienti. E’ necessario quindi ricercare nuove tipologie di trattamento - come il Tendon Neuroplastic Training - che tengano conto delle presenza di sensibilizzazione del SNC.

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Pergolizzi, J., K. Ahlbeck, D. Aldington, E. Alon, F. Coluzzi, A. Dahan, F. Huygen et al. "The development of chronic pain: physiological CHANGE necessitates a multidisciplinary approach to treatment". 2013. http://hdl.handle.net/10454/7254.

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Abstract (sommario):

No
Chronic pain is currently under-diagnosed and under-treated, partly because doctors' training in pain management is often inadequate. This situation looks certain to become worse with the rapidly increasing elderly population unless there is a wider adoption of best pain management practice. This paper reviews current knowledge of the development of chronic pain and the multidisciplinary team approach to pain therapy. The individual topics covered include nociceptive and neuropathic pain, peripheral sensitization, central sensitization, the definition and diagnosis of chronic pain, the biopsychosocial model of pain and the multidisciplinary approach to pain management. This last section includes an example of the implementation of a multidisciplinary approach in Belgium and describes the various benefits it offers; for example, the early multidimensional diagnosis of chronic pain and rapid initiation of evidence-based therapy based on an individual treatment plan. The patient also receives continuity of care, while pain relief is accompanied by improvements in physical functioning, quality of life and emotional stress. Other benefits include decreases in catastrophizing, self-reported patient disability, and depression. Improved training in pain management is clearly needed, starting with the undergraduate medical curriculum, and this review is intended to encourage further study by those who manage patients with chronic pain.

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33

Resad, Sehar. "Examining associations between psychophysical functioning and pain in young women with endometriosis and chronic pelvic pain: a pilot study". Thesis, 2017. https://hdl.handle.net/2144/23845.

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Abstract (sommario):

OBJECTIVES: This study aims to explore the relationships between preoperative psychosocial factors in relation to postoperative chronic pelvic pain (CPP) in adolescents and young women with endometriosis, which is a significant public health concern. As a pilot sample, there is large need to present preliminary data exploring the biopsychosocial correlates and possible predictors of central sensitization and CPP, which remains non-existent in the realm of adolescents and young adults with CPP secondary to endometriosis. METHODS: Eligible candidates included patients 12-22 years old who were diagnosed with CPP after laparoscopic confirmation of endometriosis. 25 successfully enrolled subjects had pre-surgical information obtained from baseline surveys and underwent a postoperative sensory protocol to assess mechanical allodynia, pressure pain sensitivity, central sensitization, and a self-report measure of pain sensitivity. Correlation calculations were conducted between pre-surgical factors (pain intensity, pain catastrophizing (PCS), and quality-of-life (from SF-36)) and post-surgical factors (pain and sensitivity thresholds as measured by QST and the PSQ) in the subject population as a whole, and in two population subgroups: those exhibiting central sensitization and those who are not. One-way ANOVA calculations and one sample t-tests were conducted to compare differences between cohorts and between abdominal and control sites for various study parameters. RESULTS: 6 of 25 (24%) subjects experienced a wind-up phenomenon during the temporal summation for pain test, serving as a surrogate for central sensitization. The differences in study parameters that this group (+CS) exhibited in comparison to the –CS group, failed to reach significance in all study parameters. Both cohorts exhibited positive correlations between pre-operative disability due to bodily pain (SF-36) and sensitivity of the abdomen, as well as negative correlations between disability due to bodily pain and pressure pain thresholds of the abdomen. The +CS cohort also exhibited a negative correlation between disability due to bodily pain and pinprick pain scores, a positive correlation between role limitations due to physical health (SF-36) and sensitivity of the abdomen, and a positive correlation between pain catastrophizing and sensitivity of the abdomen. As a whole, the subject population had significantly higher levels of catastrophizing than published means. In all cohorts, pressure pain thresholds of the abdomen were significantly lower than the control values, and PSQ-minor scores were significantly higher than published means. CONCLUSIONS: Results suggest the importance of pre-operative pain and psychosocial functioning on pain outcomes, particularly when considering subjects presenting with central sensitization, in young women with CPP secondary to endometriosis. The results indicate the need for a larger sample as well as established control values to further explore the relationships between these variables.

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34

Cherkas, Pavel S. "Trigeminal Central Sensitization and Its Modulation in Acute and Chronic Orofacial Pain Models". Thesis, 2014. http://hdl.handle.net/1807/44006.

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Abstract (sommario):

This study aimed to examine whether trigeminal nerve injury induces chronic nociceptive behaviour and central sensitization (CS) in functionally identified medullary dorsal horn (MDH) nociceptive neurons in mice, and whether CS in acute and chronic orofacial pain models and nociceptive behaviour in the chronic model are affected by systemic administration of pregabalin. Infraorbital nerve injury induced chronic facial mechanical allodynia as well as MDH CS; acute noxious tooth pulp stimulation also induced MDS CS. Systemic administration of pregabalin attenuated the nerve injury-induced allodynia as well as the MDH CS in both the chronic and acute pain models. These findings reveal that MDH CS occurs in mouse models of acute and chronic orofacial pain and that pregabalin may prove useful clinically in acute and chronic orofacial pain states.

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35

Foad, Ghazni NIOUSHA. "Functional Magnetic Resonance Imaging of Pain in the Spinal Cord and Brainstem". Thesis, 2008. http://hdl.handle.net/1974/1481.

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Abstract (sommario):

Functional magnetic resonance imaging (fMRI) studies performed to date have focused on brain structures rostral to the thalamus, although the first level of sensory information and pain transmission occurs at the spinal cord (SC). The primary goal of this project is to map activity using fMRI, from the entire cervical SC and brainstem following innocuous and noxious stimuli before and after peripheral sensitization in normal human volunteers. This study is unique in that it determines functional activity throughout the lower neural axis in response to mechanical stimuli that are perceived as painful only after sensitization. Functional MRI studies of the SC were carried out in 18 healthy individuals in a 3T Siemens Magnetom Trio. Innocuous touch and brush (n=8), and noxious touch (n=10) stimuli were applied before and after peripheral sensitization. Peripheral sensitization was induced by topical application of capsaicin. Functional image data spanned from the C7/T1 disc to the superior edge of the thalamus and analyzed using a general linear model to discriminate signal intensity changes from physiological motion. Normalized results were combined to demonstrate the number of volunteers showing activity at each location on a voxel-by-voxel basis. Areas of activity were superimposed onto anatomical transverse drawings and identified visually with comparison to several stereotaxic atlases. The results from this study confirm previous reports that a non-noxious stimulus translates into a pain response after peripheral sensitization. The brush stimulus, before sensitization activated areas in the ipsilateral dorsal horn (DH), gracile and cuneate nuclei in the medulla and areas surrounding the dorsal column medial lemniscal pathway. Peripheral sensitization produced activity in the contralateral ventral horn (VH), typical of a pain response. The innocuous von Frey stimulus produced activity in typical sensory centres in the DH and brainstem before sensitization, and areas more consistent with a noxious response after sensitization. When examining equi-nociceptive stimuli in a control versus sensitized state, the noxious touch stimuli showed similar activation patterns even though the force of the filaments were different. In all experiments there was indication of descending modulation as activity was observed in the periaqueductal gray, midbrain red nuclei and pontine reticular formation. This study demonstrates how non-painful and pain information is transmitted from the dorsal spinal horn to the brain in healthy individuals and how peripheral sensitization induces changes in non-noxious stimuli that correlate with pain sensory transmission.
Thesis (Master, Neuroscience Studies) -- Queen's University, 2008-09-24 20:13:08.655

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36

Moura, David Duarte Machado Gomes de. "Pathophysiology of Chronic Pain". Master's thesis, 2020. http://hdl.handle.net/10316/97759.

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Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina
A dor crónica é considerada uma experiência desagradável, pessoal, com carácter multidimensional, associada a um alto impacto socioeconómico, na medida em que é uma das principais causas de sofrimento, bem como de baixa produtividade e de incapacidade laboral. Devido à sua alta prevalência e impacto, constitui um dos principais motivos para a procura de cuidados de saúde por parte da população em geral. É considerada um problema de saúde pública cada vez mais frequente, afetando cerca de 40 % da população portuguesa. Pode ser definida como uma dor persistente ou recorrente, com uma duração superior a 3-6 meses, cuja função protetora deixa de existir, passando a ter um papel prejudicial para o organismo.Muito embora os processos fisiopatológicos estejam identificados e bem compreendidos nos casos da dor crónica de etiologia nociceptiva ou neuropática, há ainda dificuldade em compreender claramente os mecanismos que estão na origem de doenças como a fibromialgia, em que fenómenos de sensibilização central estão presentes, na ausência de lesão tecidular ou de compromisso nervoso. Sabe-se, porém, que a cronicidade da dor está intimamente relacionada com os fenómenos de sensibilização periférica e central que sinergicamente causam um aumento do estímulo álgico perpetuado no tempo.A presente revisão foca-se nos mecanismos fisiopatológicos que estão na base das diversas etiologias de dor crónica, explorando os fenómenos que vão desde a receção do estímulo pelos nociceptores à perceção e integração do estímulo álgico a nível cerebral.Por fim, um papel de destaque é dado à terapia farmacológica e não farmacológica da dor crónica, bem como às últimas inovações neste campo, que permitirão, a longo prazo, uma abordagem mais racional e individualizada da terapia, diminuindo a incidência de efeitos secundários desnecessários e aumentando significativamente a qualidade de vida dos doentes.
Chronic pain is considered an unpleasant, personal experience, with a multidimensional character, associated with a high socioeconomic impact, as it is one of the main causes of suffering, as well as low productivity and incapacity for work. Due to its high prevalence and impact, it is one of the main reasons for the demand for health care by the general population. It is considered a public health problem more and more frequent nowadays, affecting about 40% of the portuguese population. It can be defined as a persistent or recurrent pain, lasting more than 3-6 months, whose protective function ceases to exist, having a harmful role for the body.Although pathophysiological processes are identified and well understood in cases of chronic pain of nociceptive or neuropathic etiology, there is still difficulty in clearly understanding the mechanisms that cause diseases such as fibromyalgia in which central sensitization phenomena are present, in the absence of tissue damage or nervous compromise. However, it is known that the chronicity of pain is closely related to the phenomena of peripheral and central sensitization that synergistically cause an increase in the pain stimulus perpetuated over time.This review focuses on the pathophysiological mechanisms that underlie the various etiologies of chronic pain, exploring the phenomena that range from nociception to the perception and integration of pain stimulus at the brain level.Finally, a prominent role is given to pharmacological and non-pharmacological therapy for chronic pain, as well as the latest innovations in this field, which will allow, in the long term, a more rational and individualized approach to therapy, reducing the incidence of unnecessary side effects and significantly increasing patient’s quality of life.

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37

Mann, Mandeep Kaur. "Peripheral mechanisms of nerve growth factor-induced masticatory muscle sensitization : a model of temporomandibular disorders pain". Thesis, 2005. http://hdl.handle.net/2429/17263.

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It has been speculated that Nerve Growth Factor (NGF), a neurotrophic protein, may play a role in the pathophysiology of temporomandibular disorders (TMD). TMD are characterized by ongoing and activity-related pain in the jaw joint and muscles, and are more prevalent in women than in men. Indeed, intramuscular injection of human NGF into the masseter (jaw closer) muscle of healthy male subjects, though not acutely painful, does cause a prolonged period of activity-related muscle pain reminiscent of TMD symptoms [187]. The present study tested whether this human NGF-induced mechanical sensitization is mediated, in part, through a decrease in the mechanical sensitivity of primary afferent fibers that innervate the masseter muscle. In this randomized, blinded study, the effect of intramuscular injection of rat NGF (2.5 and 25 μg/ml) into non-inflamed masseter muscle on the mechanical threshold (MT) of rat masseter muscle afferent fibers was investigated for 6 hours post-injection. The level of plasma protein extravasation into the masseter muscle was also measured to determine if exogenous rat NGF causes muscle tissue inflammation. The results of the study indicated no treatment or sex differences in evoked afferent discharge, suggesting that administration of rat NGF did not excite afferent fibers in male or female rats. There was also no significant treatment, sex or time effect on the relative MT of masseter muscle afferent fibers. Intramuscular injection of rat NGF did not cause muscle inflammation. Nevertheless, some sex-related differences in the baseline properties of masseter muscle afferent fibers were observed. A significant log-linear relationship was identified between fiber CV and baseline MT for afferent fibers in males but not for fibers in females. There was also a positive correlation between baseline MT and estrogen levels for a subgroup of slow Aδ fibers (2-10 m/s) in females, but not in males. The finding that rat NGF does not evoke significant masseter muscle afferent discharge is consistent with previous results, which indicated injections of human NGF are not painful in human subjects. The failure of intramuscular injection of rat NGF to affect the mechanical sensitivity of masseter muscle afferent fibers suggests that central mechanisms may be more important for human NGF-induced mechanical sensitization.
Pharmaceutical Sciences, Faculty of
Graduate

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38

Becker, Susanne [Verfasser]. "Implicit operant learning of pain sensitization and habituation in healthy participants and fibromyalgia patients / Susanne Becker". 2009. http://d-nb.info/995967768/34.

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39

Tikàsz, Andràs. "Increased spinal pain sensitization : a new explanation for highly prevalent painful somatic symptoms in major depressive disorder?" Thèse, 2015. http://hdl.handle.net/1866/13480.

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Objectifs: Malgré que les patients souffrant de dépression majeure (DM) rapportent souvent des symptômes douloureux, la relation entre la douleur et la dépression n’est pas encore claire. Ce n’est que récemment que des études employant des paradigmes de sommation temporelle ont pu offrir une explication préliminaire de la cooccurrence de la douleur et de la dépression. Notre étude vise à évaluer la contribution des procédés spinaux et surpraspinaux dans la sensibilisation de la douleur dans la DM en utilisant un paradigme de sommation temporelle. Participants : Treize sujets sains et quatorze patients souffrant de DM ont été inclues dans l’analyse finale. Méthodes : Pour induire une sommation temporelle, nous avons utilisé des stimulations intermittentes du nerf sural de basses et hautes fréquences. La sensibilisation spinale de la douleur a été quantifiée en mesurant la variation de l’amplitude du réflex de retrait nociceptif (NFR) entre les deux conditions de stimulations, ainsi que la sensibilisation supraspinale de la douleur a été obtenue en mesurant le changement dans l’appréciation verbale de la douleur entre ces deux conditions. Résultats : Nous avons observé une sensibilisation plus élevée de la réponse NFR chez les patients dépressifs durant la condition de stimulation à haute fréquence, un effet qui n’a pas été reflété par une sensibilisation amplifiée des appréciations subjectives de la douleur durant l’expérience. Néanmoins, nous avons observé une association entre la sensibilisation spinale et les symptômes somatiques douloureux chez les patients DM. Conclusion : Ces résultats suggèrent une sensibilisation spinale amplifiée dans la DM, ce qui pourrait expliquer la prévalence élevée des symptômes somatiques douloureux chez ces patients.
Objectives: Although patients suffering from major depressive disorder (MDD) often complain from painful symptoms, the relationship between pain and depression has yet to be clearly characterized. Only recently have studies employing temporal summation paradigms offered some preliminary insight into the co-occurrence of pain and depression. This study sets out to evaluate the contribution of spinal and supraspinal processes in pain sensitization in MDD using a temporal summation paradigm. Subjects: Thirteen healthy controls and fourteen MDD patients were included in the final analysis. Methods: To induce temporal summation, we used low- and high-frequency intermittent stimulations of the sural nerve. Spinal pain sensitization was quantified by measuring the change in the amplitude of the nociceptive-specific flexion reflex (NFR) response, and supraspinal pain sensitization was obtained by measuring change in subjective pain rating, from the low- to high-frequency stimulation condition. Results: We found an increased sensitization in the NFR response in MDD patients in the high-frequency condition, which did not translate into an increased amplification of their subjective responses during testing. However, we found a positive association between spinal sensitization and painful somatic symptoms in MDD patients. Conclusion: Together, these results suggest increased spinal pain sensitization in MDD, which might explain the high prevalence of painful somatic symptoms in these patients.

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40

You, Dokyoung Sophia. "The Impact of Adverse Childhood Events on Temporal Summation of Second Pain". Thesis, 2012. http://hdl.handle.net/1969.1/ETD-TAMU-2012-08-11796.

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Adverse childhood events have been identified as a risk factor for developing chronic pain conditions in adulthood. However, previous studies have inconsistently supported the link between adverse childhood events and hypersensitivity to laboratory-induced pain. Therefore, this study intended to investigate the effects of adverse childhood events on temporal summation of second pain (TSSP). A group of 38 healthy and pain-free college students participated in laboratory pain tests after being screened for childhood trauma history. Half of participants (47.5% female) were positive for childhood trauma and the other half (63.2% female) reported no adverse childhood event. The laboratory pain tests measured TSSP using 10 thermal pulses per trial over four consecutive trials. The trauma group showed a tendency of greater sensitization within TSSP trials and lack of habituation over repeated TSSP trials. In sum, adverse childhood events predisposed adults to enhanced TSSP, which is potentially linked to an increased likelihood to develop chronic pain problems.

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41

Barszczyk, Andrew. "A Peptide Comprising the Src-interacting Domain of NADH Dehydrogenase Subunit 2 Alleviates Complete Freund's Adjuvant-induced Allodynia in Rats". Thesis, 2010. http://hdl.handle.net/1807/25421.

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Abstract (sommario):

Inflammatory and neuropathic pains arise in part from sensitization at nociceptive synapses in the spinal cord. Activity-dependent signaling cascades converge onto the tyrosine kinase Src, which participates in augmenting the function of N-methyl-D-aspartate receptors (NMDARs) and thus potentiates the nociceptive system. Src is capable of these effects because it is anchored to the NMDAR complex via an adaptor protein called NADH dehydrogenase subunit 2 (ND2). There is evidence that this interaction occurs between amino acids 40-49 of Src and amino acids 310-321 of ND2. I have determined that a peptide consisting of amino acids 310-321 of ND2, and affixed to the HIV Tat domain for cell permeability, is capable of alleviating tactile allodynia induced by Complete Freund's Adjuvant (CFA) in rats. Src40-49Tat was not effective in two models of inflammatory pain. This work further implicates the Src-ND2 interaction in pain hypersensitivity and suggests that Tat ND2 310-321 may alleviate it.

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42

Huntley, Devon. "Examining the role of comorbid factors in the development of central sensitization with chronic pelvic pain in cases of adolescent endometriosis". Thesis, 2018. https://hdl.handle.net/2144/30791.

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Abstract (sommario):

OBJECTIVES: This study aims to better understand the relationship between psychosocial factors and the development of chronic pelvic pain (CPP) in cases of adolescent endometriosis, specifically mood disorders, pain catastrophizing and quality of life, and to detect the development of central sensitization within this population. METHODS: Eligible candidates were patients between 14 and 22 years old with confirmed diagnosis of endometriosis and chronic pelvic pain who were enrolled in the Women’s Health Study: From Adolescence to Adulthood through the Boston Center for Endometriosis (BCE) and Boston Children’s Hospital. The administration of quantitative sensory testing (QST) to assess mechanical touch perception, pressure pain sensitivity and temporal summation was performed on 48 subjects. Pre-surgical baseline surveys, which included pain catastrophizing and quality of life measures, were obtained from the BCE. Record of diagnosed mood disorder (anxiety/depression) was obtained through medical chart review. Pearson correlations between QST measures, pain catastrophizing, presence of mood disorders or central sensitization and pre-surgical pain scores were conducted. One-way ANOVA calculations, and one sample and paired t-tests were conducted to gain further understanding of these variables as they relate to groups within the cohort. RESULTS: Regarding QST measures, 23 subjects (47.9%) produced a wind-up phenomenon from temporal summation during QST administration, which serves as a surrogate for the presence of central sensitization (+CS). Pressure sensation and pain scores correlated at all test sites (lower and upper abdomen, as well as finger control site) and wind-up phenomenon correlated in the lower and upper abdomen throughout the cohort. For the presence of mood disorders, anxiety and depression were equally distributed across the +CS and –CS groups. Review of pre-surgical pain scores and pain catastrophizing (PCS) within the cohort had significant correlations between pre-surgical pain and PCS subsets of rumination and magnification. PCS total and subset scores also correlated to +CS. One-way ANOVA calculations showed the cohort as a whole presented with clinically significant helplessness. CONCLUSIONS: Results encourage further investigation of the relationship between endometriosis, comorbid conditions, environmental factors and the development of CPP within the adolescent population. More detailed data regarding mental health and documentation of condition progression, as well as establishment of health control values and sample growth are encouraged for the continued progress of this project.
2020-07-03T00:00:00Z

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Stemkowski, Patrick. "The effect of long-term interleukin-1 beta exposure on sensory neuron electrical membrane properties: implications for neuropathic pain". Phd thesis, 2011. http://hdl.handle.net/10048/1713.

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The effect of interleukin-1 beta (IL-1β) on the electrical properties of sensory neurons was assessed at comparable levels and exposure times to those found in animal models of neuropathic pain. Experiments involved whole cell current- or voltage-clamp recordings from rat dorsal root ganglion (DRG) neurons in defined medium, neuron enriched cultures. 5-6 days exposure to 100 pM IL-1β produced neuron specific effects. These included an increase in the excitability of medium diameter and small diameter isolectin B4 (IB4)-positive neurons that was comparable to that found after peripheral nerve injury. By contrast, a reduction in excitability was observed in large diameter neurons, while no effect was found in small diameter IB4-negative neurons. Further characterization of changes in medium and small IB4-positive neurons revealed that some, but not all, effects of IL-1β were mediated through its receptor, IL-1RI. Using appropriate voltage protocols and/or ion substitutions, it was found that neuron specific changes in several ionic currents, including alterations in hyperpolarization activated inward current (IH) and decreases in various K+ currents contribute to the increased excitability produced by IL-1β. Overall, these studies revealed that: 1. The effects of long-term exposure of DRG neurons to IL-1β are reflective of the enduring increase in primary afferent excitability reported after peripheral nerve injury. This expands the recognized role of IL-1β in acute inflammatory pain to neuropathic pain. 2. Hyperexcitability in medium neurons exposed to IL-1β likely includes mixed populations of neurons corresponding to nociceptive and non-nociceptive primary afferent fibres and, therefore, has relevance to hyperalgesia and allodynia, respectively. 3. The responsiveness of small IB4-positive neurons, but not IB4-negative, to prolonged IL-1β exposure is consistent with the suggestion that small IB4-negative afferents are involved in inflammatory pain, while small IB4-positive afferents are involved neuropathic pain. 4. The identification of receptor mediated effects and several contributing ionic mechanisms, may have relevance to the development of new therapeutic approaches to neuropathic pain. 5. IL-1β can contribute to increased neuronal excitability by mechanisms that are independent of IL-1RI signalling. This should be taken into account when targeting IL-1β, or more specifically IL-1RI, in the management of neuropathic pain.

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Siebertz, Mathias Walter. "Zentrale Sensibilisierung, Schmerzlokalisation und -ausdehnung bei Arthrose des Hüftgelenks". Doctoral thesis, 2020. http://hdl.handle.net/21.11130/00-1735-0000-0005-13A7-9.

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45

Farrell, Kristen Elise. "Investigation of visceral sensory processing mechanisms in the superficial dorsal horn of the spinal cord". Thesis, 2017. http://hdl.handle.net/1959.13/1335508.

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Research Doctorate - Doctor of Philosophy (PhD)
Pain is the most common symptom of inflammatory diseases of viscera or the gastrointestinal tract. Importantly, pain occurs during active disease and often persists during clinical remission. The specific functional mechanisms underlying the development and maintenance of visceral pain are not known. To date, functional studies have focussed on the peripheral nervous system, using gut-nerve preparations, in animal models of visceral hypersensitivity. Clinical studies, however, suggest changes in the central nervous system CNS contribute to altered sensory perception in visceral inflammation. This thesis first explored the central mechanisms underlying visceral hypersensitivity in animal models of visceral inflammation. I completed a systematic review and found extensive evidence for CNS plasticity, particularly within the spinal cord dorsal horn (DH), in animal models of visceral inflammation. I also found no studies had examined the functional properties of DH neurons during visceral inflammation even though these properties are critical determinants of neuron output and altered signaling to the brain. Next, to study the functional properties of neurons that received colonic inputs, I developed an in vivo preparation that permitted wholecell electrophysiological recording from DH neurons in intact adult mice. I showed that in naïve animals, neurons with colonic inputs responded to visceral stimulation with predominately subthreshold synaptic activity. Their membrane and synaptic properties also differed from neurons lacking colonic inputs. I next repeated these experiments in a mouse model of mild colitis. During colitis the responses of DH neurons to visceral and cutaneous stimulation and their synaptic properties were altered in a manner that would make DH neurons more excitable. Conversely, several measures of intrinsic excitability were decreased following colitis. These data suggest visceral inflammation has complex effects on the functional properties of DH neurons and likely reflects the crucial role the spinal cord plays in modulating sensory inputs from the viscera.

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Rialland, Pascale. "Métrologie de la douleur animale : validation sur des modèles de douleur viscérale bovine et articulaires canins". Thèse, 2013. http://hdl.handle.net/1866/11441.

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La douleur est une expérience multidimensionnelle comportant des aspects sensoriels, émotionnels et cognitifs. Théoriquement, des méthodes de mesures comportementales, physiologiques, neurophysiologiques et sensorielles peuvent quantifier la douleur. Peu d’études ont étudié la validation des mesures utilisées en médecine vétérinaire. La recherche combine les travaux de Maîtrise et de Doctorat, traite en partie de la validité de méthodes. Dans cet objectif, nos travaux de recherche étudiaient la validité de méthodes comportementales, physiologiques et neurophysiologiques usuelles pour la mesure de la douleur en comparant les expressions de douleur (vache et chien) chez des animaux contrôle par comparaison à des animaux sous analgésie préventive ou sous traitement curatif suivant une douleur induite par chirurgie (modèles de douleur viscérale bovine ou orthopédique canine) ou causée par une maladie naturelle (arthrose canine). Une première étude comparait les mesures de la douleur entre les vaches du groupe placebo et celles sous analgésie postopératoire sur une durée de 21 jours suivant l’induction d’une douleur viscérale chronique. Les vaches du groupe placebo ont présenté une plus forte sensibilité à la douleur et une diminution de la noradrénaline et de la transthyrétine mesurées dans le liquide cérébro-spinal, une diminution de l’activité motrice (AM) (moindre que dans les groupes avec analgésie), de l’agitation enregistrée par vidéo-analyse et une augmentation du stress selon la mesure de l’activité électrodermique (AED). Les méthodes d’intérêt identifiées étaient les marqueurs spinaux, la mesure de la sensibilisation, de comportements par vidéo-analyse et de l’AM par bio-télémétrie. En utilisant des méthodes semblables à celles précédemment décrites, deux études expérimentales de douleur orthopédique ont été réalisées afin de comparer les réponses à la douleur entre des chiens traités avec une analgésie préventive (opioïdes et anti-inflammatoires, étude #2) ou un biphosphonate (tiludronate, étude #3) par comparaison à des chiens contrôles. Seules les échelles de douleur étaient différentes entre les études de recherche. Pour l’étude #2, les ii chiens sous analgésie ont présenté de plus faibles scores de douleur mesurés avec l’échelle de douleur nommée 4A-VET et ceci simultanément à une faible réponse de l’AED une heure après la chirurgie de trochléoplastie. La fréquence du comportement spontané de ‘la marche avec plein appui de la patte opérée’ mesurée à l’aide de la vidéo-analyse augmentait chez les chiens sous analgésie préventive 24 heures après la chirurgie. L’étude #3 démontrait surtout l’apparition de sensibilisation centrale (à la fois par l’évaluation sensorielle quantitative et les marqueurs spinaux) chez les chiens contrôle, 56 jours après l’induction d’arthrose chirurgicale. Ainsi, les chiens traités avec le tiludronate ont présenté une différence sur la substance P et la transthyrétine cérébro-spinale, une diminution de la sensibilisation périphérique, plus d’appui de la patte opérée lors de la marche selon la mesure du pic de force verticale (PFV), une augmentation de la fréquence de ‘la marche avec plein appui de la patte opérée’. La sensibilisation centrale était associée à la diminution de PFV, et une augmentation de l’AED et du comportement spontané de ‘la marche avec plein appui de la patte opérée’. Pour l’étude #4, la validité et la sensibilité des méthodes ont été évaluées dans une condition d’arthrose naturelle chez des chiens traités avec une diète enrichie en moule verte, un produit ayant des effets anti-inflammatoires et chondroprotecteurs attendus. Les chiens traités présentaient une diminution des scores de douleur via l’échelle nommée CSOM, une augmentation de PFV et une augmentation de l’AM. Dans l’ensemble, les résultats confirment que la vidéo-analyse évaluait la douleur de façon objective et pour des modèles différents de douleur et les marqueurs spinaux sont prometteurs. Le PFV était spécifique de la douleur orthopédique. La sensibilisation était présente lors de douleur pathologique. L’AED n’est pas valide pour la mesure de la douleur. La baisse d’AM suggèrerait un comportement de douleur. Les études étaient exploratoires pour les échelles de douleur en raison de leur niveau (débutant) de développement et du manque d’informations sur les qualités métrologiques de ces mesures.
Pain is a multidimensional experience involving sensitive, emotional and cognitive components. Theoretically, there are multiple methods by which pain can be assessed including sensitive, behavioural, physiological, or neurophysiological measurements. However, little work has been done to validate these measurements in veterinary medicine. The presented research program including both Master and Doctorate works was intended to address partially this paucity of research. For this purpose, our work would validate some behavioural and physiological methods of pain assessment by contrasting pain expressions (cows and dogs) in painful animals (negative control) and animals treated with preventive analgesic or curative treatment following surgery-induced (bovine visceral and canine orthopaedic models) pain or natural occurring disease (osteoarthritis in dog). A pain study was first conducted to compare measurements of placebo treated-cows with postoperative analgesic treated-cows during 21 days following surgical induction of sustained visceral pain. Placebo treated-cows were found to have increased pain sensitization and decreased concentration of cerebrospinal fluid noradrenaline and transthyretin, less motor activity (but higher than in analgesic groups), more restlessness recorded with video-analysis and increased partially stress with measurement of electrodermal activity (EDA). This first study allowed a selection of methods of interest for pain evaluation including spinal biomarkers, measurement of sensitization, behavioural recording with video-analysis and motor activity with biotelemetry. Therefore, two canine pain experiments, with use of similar methods of pain assessment presented above, were performed to compare responses to pain between preventive analgesics treated-dogs (opioids and anti-inflammatory drug, study #2) or a bisphosphonate (tiludronate in study #3) with placebo-treated dogs. Only the pain scales were different among the projects. For project #2, analgesic treated-dogs were found to have lower pain scores measured with the so-called 4A-VET postoperative pain scale while simultaneously exhibiting reduction of EDA response up to 1 hour following trochleoplasty. In addition, the occurrence rate of the spontaneous behaviour ‘Walking with full weight bearing of the operated leg’ recorded with video-analysis, was higher in analgesic treated-dogs when compared with the placebotreated dogs at 24 hours post trochleoplasty. The pain study #3 was then conducted and demonstrated central sensitization (assessed with quantitative sensory testing and spinal biomarkers) in all control dogs at 56 days post induction of the canine osteoarthritis pain model. Nevertheless, tiludronate treated-dogs were found to have different spinal biomarkers (substance P and transthyretin), decreased peripheral sensitization, more peak vertical force (PVF), which is a kinetic gait parameter, and increased occurrence rate of ‘Walking with full weight bearing of the operated leg’. Interestingly, the central sensitization was associated negatively with PVF and positively with both EDA and ‘Walking with full weight bearing of the operated leg’. Finally, a fourth pain study was conducted to examine whether some of the methods performed validity and sensitivity in clinical condition with osteoarthritic dogs. For this purpose, osteoarthritic dogs were treated with a green-lipped mussel enriched-diet, having both anti-inflammatory and chondroprotective expected activities. The treated-dogs were found to have low pain scores measured with the pain scale for owner named CSOM, increased PVF and motor activity. Indeed, CSOM scores were associated with both PVF and motor activity. Taken together, the results suggest that video-analysis would assess pain expression through objective, predictive and unique evaluation whatever the species or the model, whereas spinal biomarkers are promising. The PVF changes were related to orthopaedic pain. Sensitization appeared to be common to the pathological pain pattern. The EDA was not validated for pain assessment in animals. Decreased motor activity is pain suggestive. Psychometric evaluation of the pain scales remained only exploratory at this (early) stage of development and knowledge of the present pain scales.

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Otis, Colombe. "Métrologie de la douleur animale sur modèles expérimentaux : développement et validation de biomarqueurs neuroprotéomiques". Thèse, 2017. http://hdl.handle.net/1866/21067.

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Hollasová, Sára. "Proměnné predikující efekt operace u pacientů s bolestí zad". Master's thesis, 2020. http://www.nusl.cz/ntk/nusl-435778.

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Variables predicting the effects of surgery in patients with low back pain Abstract The theoretical part of the thesis summarizes the knowledge about pain and its types, especially chronic pain. Than we focus on low back pain and currently used approaches in the treatment of this syndrome. In this work we summarize the influence of central sensitization and adverse life experineces and posttraumatic stress disorder on pain (especially low back pain). In the practical part, we investigated the effect of central sensitization and adverse life events and posttraumatic stress disroder on the effect of spinal surgery in low back region. The results were obtained using Central Sensitization Inventory (CSI), PTSD Cecklist dor DSM-5 (PCL- 5) a Life Event Checklist (LEC-5 Standard), Short Form 36 Helth Survey Questionnaire (SF- 36), NASS Lumbar Spine Questionnaire. The obtained data were statistically evaluated and processed. Higher scores of CSI and LEC-5 (more adverse life events) were both statistically significantly correlated with worse low back surgery outcomes. At the same time, a statistically significant relationship between PCL-5 (checklist of PTSD symptoms) and CSI was confirmed. Keywords Pain, central sensitization, adverse life experiences, adverse life events, PTSD, posttraumatic stress disorder,...

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Park, Kellie Adrienne. "Cellular Mechanisms Mediating the Actions of Nerve Growth Factor in Sensory Neurons". Thesis, 2007. http://hdl.handle.net/1805/1127.

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Indiana University-Purdue University Indianapolis (IUPUI)
Nerve growth factor (NGF) is a neurotrophin upregulated with injury and inflammation. Peripheral administration of NGF causes hyperalgesia and allodynia in animals. Blocking NGF signaling reverses these effects. At the cellular level, chronic exposure of sensory neurons to NGF enhances expression the neurotransmitter, calcitonin gene-related peptide (CGRP). Acute exposure to NGF increases capsaicin-evoked CGRP release from sensory neurons in culture. Thus, NGF increases peptide release from neurons by: (1) increasing expression of peptides, and/or (2) altering their sensitivity. The increase in peptide outflow by either mechanism could contribute to development of hyperalgesia and allodynia. The signaling cascades mediating the actions of NGF in sensory neurons are unclear. Therefore, experiments were designed to determine which pathways regulate changes in iCGRP content and evoked release from primary sensory neurons in culture. The Ras/MEK/ERK cascade was identified as a possible regulator of iCGRP expression in response to NGF. To test this pathway, it was manipulated in neurons by (1) expression of dominant negative or constitutively active isoforms of Ras, (2) farnesyltransferase inhibition, (3) manipulation of the RasGAP, synGAP, and (4) blocking MEK activity. When the pathway was blocked, the NGF-induced increase in iCGRP expression was attenuated. When the Ras pathway was activated, iCGRP expression increased. These data indicate that Ras, and downstream signaling kinases, MEK and ERK, regulate the NGF-induced increases in CGRP in sensory neurons. To determine which pathway(s) regulate the increase in capsaicin-evoked iCGRP release upon brief exposure to NGF, the Ras/MEK/ERK pathway was manipulated as described above, and pharmacological inhibitors of the PI3 kinase, PLC, and Src kinase pathways were used. There were no differences observed in NGF-sensitization when the Ras and PI3 kinase pathways were inhibited, suggesting these two pathways were not involved. However, when the Src kinase inhibitor PP2 was used, the NGF-induced increase in release was completely blocked. Furthermore, the PKC inhibitor, BIM, also inhibited the sensitization by NGF. This data indicate Src and PKC regulate of sensitivity of sensory neurons in response to brief exposure to NGF. Thus, there is differential regulation of iCGRP content and evoked release from sensory neurons in response to NGF.

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