Dissertations / Theses on the topic 'Hyperalgesia'
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McConaghy, Paul M. "Secondary hyperalgesia and postoperative pain." Thesis, Queen's University Belfast, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387878.
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Ramos, Khara M. "Spinally-mediated hyperalgesia in experimental diabetes." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3258831.
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Thesis (Ph. D.)--University of California, San Diego, 2007.Title from first page of PDF file (viewed June 8, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 193-221).
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Stein, Alexander T. "Nerve growth factor produces hyperalgesia through phosphoinositide 3-kinase-dependent recruitment of TRPV1 ion channels /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/10631.
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MIZUMURA, KAZUE. "Peripheral Mechanism of Hyperalgesia : Sensitization of Nociceptors." Nagoya University School of Medicine, 1997. http://hdl.handle.net/2237/16753.
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Freshwater, Jason D. "Spinal mechanisms of hyperalgesia in experimental diabetes /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2004. http://wwwlib.umi.com/cr/ucsd/fullcit?p3120722.
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Isherwood, Ruth Jayne. "Opioid-related side-effects and opioid-induced hyperalgesia." Thesis, University of Glasgow, 2015. http://theses.gla.ac.uk/6598/.
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Introduction: Opioids are widely used for the management of cancer and chronic non-cancer pain and the maintenance management of patients with a history of substance misuse. Increasingly the use of opioids is being scrutinised as patients are prescribed opioids for longer periods and the long-term effects of the opioids becomes clinically more relevant and evident. Our work has explored the prevalence of opioid-related side-effects in patients who are prescribed opioids and explored the clinically relevant phenomenon of opioid-induced hyperalgesia. . Methods: Patients were recruited who were prescribed opioids for the management of cancer and non-cancer pain or substance misuse. Quantitative data was collected to explore the prevalence and severity of opioid related side-effects, the impact of opioids on cognitive function and the effect of opioids on peripheral nerve function through quantitative sensory testing. Testing the sensory processing of patients who are on opioids has revealed altered thermal thresholds and the presence of wind-up at non-painful sites indicating central sensitisation. Qualitative description was used to explore the patient experience of an episode of opioid toxicity. Results: Patients have a significant burden of side-effects which have often not been recognised by clinicians. Using the Addenbrooke’s Cognitive Examination much more cognitive impairment has been revealed than has previously been recognised. Altered thermal thresholds and wind-up at non-painful sites suggests altered pain processing as a result of opioids. Themes from the qualitative description highlighted the coping strategies patients’ develop when managing with significant side-effects and toxicity, the covert self-management of their pain and the need to exert control. One of the most significant findings from the qualitative research was the finding of altered sensation and pain description associated with other features of opioid toxicity. Conclusions: The impact of opioids on the cognitive function of patients has significant implications in terms of patients’ involvement in decision-making and functioning in everyday life. The qualitative data reflects the burden of side effects and the descriptions of patients suggest that opioid-induced hyperalgesia exists as part of the spectrum of opioid toxicity. This finding may help physicians identify patients who are developing opioid-induced hyperalgesia and allow them to intervene earlier with a proactive approach.
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McNamee, Kay Edwina. "The role of IL-17 in inflammatory hyperalgesia." Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/7066.
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Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects up to 1% of the population. The importance of tumour necrosis factor (TNF) in RA has been established and anti-TNF biologics have proved to be highly effective in reducing inflammation. However, a proportion of RA patients fail to adequately respond to anti-TNF and even those who do respond have residual pain. This has prompted the investigation into other cytokines, such as interleukin-17 (IL-17), as potential new targets. This study sought to investigate the contribution of IL-17 to acute or chronic hyperalgesia. C57BL/6 mice were injected with recombinant IL-17. This induced a transient hyperalgesia, which was found to be dependent both on neutrophil migration and signalling through TNFR1. Using the air pouch model of cell migration, it was confirmed that the cell infiltration was associated with increased expression of the chemokine keratinocyte attractant (KC). These results suggest that IL-17 induces acute hyperalgesia by inducing TNF from resident cells. To investigate IL-17 and chronic hyperalgesia, the collagen induced arthritis mouse model (CIA) was used. IL-17RA was found to be up regulated in both the paw and in the dorsal root ganglia in arthritis, suggesting a role for IL-17 in chronic hyperalgesia. IL-17 blockade proved to be anti-arthritic and analgesic during CIA and potently reduced expression of pro-inflammatory cytokines. This study confirms that IL-17 contributes to acute and chronic hyperalgesia but acts in part via the induction of TNF.
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Vardanyan, Anna. "Opioid-induced Hyperalgesia: Underlying Mechanisms and Clinical Relevance." Diss., The University of Arizona, 2007. http://hdl.handle.net/10150/195034.
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Metastatic bone cancer causes severe pain that is primarily treated with opioids. A recently developed model of bone cancer pain was used to evaluate the effects of sustained morphine treatment. In cancer-treated mice, morphine enhanced spontaneous and evoked pain; these effects were dose-dependent and naloxone-sensitive. SP and CGRP positive DRG cells did not differ between sarcoma or control mice, but were increased following morphine in both groups. Morphine increased ATF-3 expression only in DRG cells of sarcoma mice. Morphine did not alter tumor growth in vitro or in vivo but increased sarcoma-induced bone destruction and incidence of spontaneous fracture in a dose- and naloxone-sensitive manner. Morphine increased osteoclast activity suggesting enhancement of sarcoma-induced osteolysis. Thus, morphine treatment may "add-on" additional mechanisms of pain beyond those induced by sarcoma. Despite the potential clinical significance, the exact mechanisms of opioid-induced hypersensitivity remain unknown. The vanilloid 1 receptor (TRPV1) is a molecular integrator of noxious stimuli. Sustained morphine elicited thermal and tactile hypersensitivity in WT, but not TRPV1 KO mice. Sustained morphine enhanced capsaicin-induced flinching and plasma extravasation in rats, indicating increased activity of these receptors in the periphery. Immunohistochemical studies indicate increase in TRPV1 expression in DRG and sciatic nerve, but not spinal cord, suggesting increased trafficking of TRPV1 channel to the periphery. Possible mechanisms of this enhanced expression and function of TRPV1 channels is activation of p38 MAPK. Sustained intrathecal infusion of p38 MAPK inhibitor prevents morphine-induced hypersensitivity and enhanced capsaicin-induced flinching, indicating the role of p38MAPK in the development of morphine-induced pain, possibly through sensitization of TRPV1 receptors. Acute administration of p38 MAPK inhibitor reversed morphine-induced pain suggesting the importance of p38 MAPK in the maintenance of morphine-induced hypersensitivity, likely through activation of TRPV1 channel. Sustained morphine also up-regulates NGF content in skin, which is then transported to DRG neurons where phosporilation of p38MAPK takes place. Single injection of anti-NGF peptibody blocked the development of morphine-induced hypersensitivity, enhanced capsaicin-induced flinching and plasma extravasation. Co-treatment with these compounds blocks the development of morphine-induced hyperalgesia and may optimize treatment of chronic pain states, like bone cancer pain.
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Ernberg, Malin. "Significance of serotonin for pain, allodynia, and hyperalgesia in the human masseter muscle /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3779-6/.
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Duedahl, Tina Hoff. "Anti-hyperalgesic drugs in postoperative pain /." Cph. : The Danish University of Pharmaceutical Sciences, Department of Pharmaceutics, 2005. http://www.dfuni.dk/index.php/Tina_Hoff_Duedahl/1732/0/.
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Cuellar, Jason M. "Spinal mechanisms of pain, hyperalgesia and modulation by anesthetics /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2004. http://uclibs.org/PID/11984.
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Chen, Chao-Chen. "Role of VPM thalamus in mechanical sensitivity and hyperalgesia." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ48754.pdf.
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Osborne, Michael G. "The role of nitric oxide in carrageenan-induced hyperalgesia." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0025/MQ50848.pdf.
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Wanigasekera, Vishvarani A. "Imaging opioid mediated analgesia and hyperalgesia in healthy humans." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526127.
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Campos, Christopher Roman. "Central regulation of Blood Brain Barrier integrity during hyperalgesia." Diss., The University of Arizona, 2009. http://hdl.handle.net/10150/195377.
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The blood-brain barrier (BBB) is located at the level of the cerebral microcapillaries, and functions to maintain environmental homeostasis by allowing the neurons access to the required nutrients and enabling the exchange of metabolic waste. BBB dysfunction has been observed in a number of pathophysiologic statres including peripheral inflammatory pain (Huber et al., 2001b). Using the lamda-carrageenan inflammatory pain (CIP) model, we observed alterations in the tight junction (TJ) proteins paralleled by an increase in BBB permeability to [14C] sucrose. The mechanisms by which these perturbations occurred remain to be elucidated. In the current study, we investigate the central mechanism for the BBB perturbations under CIP. It is our hypothesis that the modulations of the BBB under CIP, are mediated via a central signaling pathway. First, to investigate the involvement of neuronal input from pain activity on alterations in BBB, we developed a method for inhibiting the nociceptive input from the paw. Using a perineural injection of 0.75% bupivacaine into the right hind leg prior to CIP, we were able inhibit development thermal hyperalgesia induced by CIP, as tested by infrared heat stimulus, without effecting edema formation 1 h post CIP. Upon inhibition of nociception under CIP, there was an attenuation of both the changes in permeability and the changes in tight junction protein expression, with both returning to control levels. Next, we investigated intercellular adhesion molecule-1 (ICAM-1), a key signaling protein at the BBB, which in the presence of proinflammatory mediators, increases in expression leading to the activation of signaling pathways as well as morphological changes. We found a region specific increase in ICAM-1 mRNA and protein expression following CIP which directly correlated with increased expression of activated microglia. Finally, we investigated the influence activated microglia had on BBB permeability. Using an 0.150 mg intrathecal bolus injection of minocycline, a potent inhibitor of microglia activation (Klein and Cunha, 1995), we were able to inhibit the increased expression of activated microglia, and saw an attenuation of permeability to control levels. These findings suggest CIP induced BBB disruption is localized and has a central-mediated component independent of peripheral influence.
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Whay, Helen Rebecca. "The perception and relief of pain associated with lameness in dairy cattle." Thesis, University of Bristol, 1998. http://hdl.handle.net/1983/fff8dd19-9805-4315-9c9a-29148cb48a89.
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Cattle lameness is the biggest disease problem facing dairy farmers in the United Kingdom at this time. Current figures show that over 50 per cent of dairy cattle become clinically lame each year. In addition to the loss of productivity associated with lameness the question of whether the animals welfare is compromised through pain and suffering associated with lameness needs to be addressed. Also how relief from such suffering can be approached using the resources available to the modem dairy farmer and veterinary surgeon. Many diseases of the claws and lower limbs of cattle with differing aetiology and pathogenesis are brought together under the heading of lower limb lameness. Fifteen different lesions are commonly seen with many more occurring sporadically. The lameness ranges from acute to chronically persistent often with similar lesions seen in repeated lactations. During an episode of lameness the cow is frequently expected to continue to compete for nutrition and lying space within the herd environment and, during the summer months, to walk long distances to and from pasture. This is a management approach which is likely to decrease the welfare and increase the suffering of a lame dairy cow. The aim of the study was to evaluate the changes in behaviour of dairy cattle which are associated with lameness by locomotion and lameness scoring, the observation of spontaneous behaviours and changes in demeanour. To then relate these changes to parameters such as nociceptive threshold, lesion type and claw pathology, endocrine response and changes in weight bearing. Also, to study the effects of analgesics on these behaviours and objective parameters. In so doing to build up a picture of the animal's perception of the pain associated with lameness. The results showed that parturition represented a period of high risk for the appearance of claw lesions and the onset of lameness in dairy heifers. Clinical lameness in lactating dairy cows was associated with a decrease in mechanical nociceptive thresholds indicating the presence of hyperalgesia in these animals. The hyperalgesia persisted in cattle with chronic claw diseases up to 28 days after the lesion was treated and behavioural signs of lameness were no longer present but was not later detected in those individuals with acute digital tissue infections. The administration of a Non-Steroidal Anti-inflammatory Drug with analgesic properties to cattle with a hind limb lameness resulted in a significant modulation in the level of hyperalgesia over a 28 day period. This modulation was not observed in lame cattle who were given a control treatment of Sterile Saline in association with a programme of conventional treatment. Postural changes associated with lameness were ameliorated through a conventional treatment programme while the demeanour of the lame animals was seen to improve when offered analgesia concurrently with treatment. In summary, chronically lame cattle were found to be in a persistent hyperalgesic state indicative of pain. Further evidence of suffering was provided by behavioural observation and the evidence of some, but not total, relief from pain through the administration of analgesia. It could therefore be concluded that there is pain associated with lameness which is likely to cause the animal suffering. In the future a more integrated approach to the treatment, management and analgesia of lame cattle is required to provide relief from this suffering
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Jaggar, Sian Isobel. "Studies of inflammatory hyperalgesia with special reference to the viscera." Thesis, Imperial College London, 2000. http://hdl.handle.net/10044/1/7989.
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Bedwell, Gillian Jennifer. "The effect of stimulus threat on experimentally induced secondary hyperalgesia." Master's thesis, Faculty of Health Sciences, 2020. http://hdl.handle.net/11427/32423.
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Background Neuropathic pain affects 7 – 10% of people and responds poorly to pharmacotherapy. Numbers needed to treat for first line drugs range from 4 – 8. Therefore, there is an obvious need for improved understanding of the mechanisms of neuropathic pain to inform improved treatments. Mechanistic research on neuropathic pain frequently uses a human surrogate model of secondary hyperalgesia that is a common feature of neuropathic pain. The value of experimentally inducing secondary hyperalgesia is that one can then test the influence of different pharmacological and nonpharmacological interventions. This may shed some light on the physiological mechanisms within the spinal cord, which possibly also translates to the effects of the interventions on other pathways that are involved in processing signals that may be related to pain. Additionally, pain is known to be influenced by the threat value of the situation. Many South Africans live under constant threat: less than a third of South Africans feel safe walking alone at night. This constant threat may be perpetuating the pain problem in South Arica. However, the mechanism by which threat achieves this influence on pain is unclear. This project is focused on one possible mechanistic hypothesis: that threat influences pain by affecting central physiological changes within the dorsal horn of the spinal cord. These central changes often present clinically as secondary hyperalgesia. A thorough understanding of these mechanisms will inform improved treatment strategies. Methods Phase one: systematic review and meta-analysis The aim of this systematic review was to identify, describe, and compare methods that have been used to manipulate experimentally induced secondary hyperalgesia in healthy humans. A systematic search strategy (conducted on 01 October 2019) was supplemented by reference list checks and direct contact with identified laboratories to maximise the identification of data reporting the experimental manipulation of experimentally induced secondary hyperalgesia in humans. Studies were only included if they were published and in-press or accepted records for which the title, abstract, and full-text versions were available in English. Duplicate screening, risk of bias assessment, and data extraction procedures were used. Risk of bias was appraised for the following domains: selection, performance, detection, attrition, measurement, reporting, and other sources of bias. Data were extracted using a standardised data extraction form. This form was piloted and refined beforehand. Authors were asked to provide data were necessary. Data were pooled by method of v manipulation and outcome (intensity of secondary hyperalgesia, area of secondary hyperalgesia, or both). Phase two: experimental paradigm An experimental study was developed and conducted to investigate the effect of a stimulus threat on secondary hyperalgesia. The aim of this study was to investigate the effect of a manipulation of the threat value of a stimulus on experimentally induced secondary hyperalgesia in healthy human volunteers. All participants underwent a sham skin examination (the threat stimulus) at both the experimental and control sites. Through this sham skin examination, participants were informed that their skin integrity was fragile at the experimental site and robust at the control site. Secondary hyperalgesia was induced with high-frequency electrical stimulation at both the experimental and control site. Sensory testing was conducted at the experimental and control site, providing a withinsubject comparison of the intensity and area of secondary hyperalgesia at each site. It was hypothesised that greater threat will be associated with (hypothesis 1) greater intensity and (hypothesis 2) greater surface area of induced secondary hyperalgesia. Results Phase one: systematic review Twenty-one studies with non-pharmacological manipulations were included. Nine (out of 21) studies assessed intensity of secondary hyperalgesia after manipulation. Nicotine deprivation and negative expectations about the induction increased the intensity of secondary hyperalgesia. Three studies using attentional modulation and cognitive loading reported conflicting results with two studies having no effect and the other reporting a decrease in the intensity of secondary hyperalgesia. Emotional disclosure decreased the intensity of secondary hyperalgesia at four days and at one month after the manipulation. Hot/cold application, and verbal suggestion had no effect on the intensity of secondary hyperalgesia. Seventeen (out of 21) studies assessed area of secondary hyperalgesia after manipulation. Nicotine deprivation and sleep deprivation increased the area of secondary hyperalgesia. Hyperbaric oxygen therapy, cognitive behavioural therapy, emotional disclosure, spinal manipulation, transcranial direct current stimulation, and placebo analgesia decreased the area of secondary hyperalgesia. Interestingly, the effects of emotional disclosure and hyperbaric oxygen therapy were evident one month after manipulation. Acupuncture had no significant effect on the area of secondary hyperalgesia. Four studies assessed the effect of hot/cold application. Three studies reported no effect and one study reported an increase in the area of secondary hyperalgesia after cold application.
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de, Silva-Rossdeutscher Evelyn. "Hyperalgesia associated with the iontophoresis of opioids in the skin." Thesis, de Silva-Rossdeutscher, Evelyn (2000) Hyperalgesia associated with the iontophoresis of opioids in the skin. PhD thesis, Murdoch University, 2000. https://researchrepository.murdoch.edu.au/id/eprint/52296/.
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Chronic pain is a part of many disorders and illnesses. Systemic treatment with opioids, although effective in controlling pain, very often produces uncomfortable side effects. Non-invasive methods of drug delivery which minimize systemic side effects are therefore important for the management of chronic pain. Iontophoresis is one such method; in the current project, the effects of iontophoresis of opioids on local pain control were investigated in 8 experimental studies on healthy volunteers.
In Study 1, the effects of morphine iontophoresis in capsaicin-inflamed skin were examined. The optimal dose of morphine iontophoresis (1, 2, 4 or 8 minutes) required to inhibit thermal and mechanical hyperalgesia evoked by radiant heat and a von Frey filament was investigated 10 and 30 minutes following the final iontophoresis. Saline was iontophoresed for the same duration as morphine and was used as the control. Unexpectedly, the iontophoresis of morphine produced significantly greater thermal hyperalgesia than saline, with the 2 minute dose producing the greatest hyperalgesia. Some indication of nonspecific effects of iontophoresis were also detected at the saline sites. Sites iontophoresed with morphine produced greater mechanical hyperalgesia than sites iontophoresed with saline when tested after 30 minutes. It was suspected that the hyperalgesia found was due to histamine release because of the blistering observed at morphine iontophoresis sites.
Study 2 was carried out to investigate the effects of pretreating 2 minute iontophoretic doses of morphine and methadone with naloxone iontophoresis. Methadone was introduced because it was reported to not release histamine. Nonspecific effects of iontophoresis were examined by introducing control sites that did not receive any iontophoresis. The specific effect of a 6.15 minute naloxone iontophoresis was also investigated on thermal and mechanical hyperalgesia using the same sensory tests as in Study 1. Heat pain thresholds were lower at the saline sites than at control sites tested 10 minutes after the final iontophoresis. There were no nonspecific effects of iontophoresis on mechanical hyperalgesia. Iontophoresis of naloxone on its own did not affect thermal or mechanical hyperalgesia. Although pretreatment of morphine and methadone sites with naloxone did not influence the heat pain threshold, pretreatment of morphine sites with naloxone produced significantly less mechanical hyperalgesia than pretreatment with saline. A similar effect was detected for methadone when sites were tested after 30 minutes. Although naloxone pretreatment resulted in slightly fewer cases of blistering, it did not altogether prevent the wheal formation resulting from morphine iontophoresis.
Study 3 was carried out to test whether a 4 minute or 30 second iontophoresis was required for methadone to produce analgesia in capsaicin-inflamed skin. Unlike morphine, methadone did not produce hyperalgesia when tested 10 minutes after the iontophoresis. Therefore since we were looking for analgesia, sensory testing was conducted 10 minutes after the final iontophoresis in this study and in all subsequent studies. A second measure of heat pain was introduced, that of suprathreshold heat pain ratings to 35°C) 40°C and 45°C held for 7 seconds on each site. In addition, mechanical pressure pain thresholds were measured using a pressure algometer in place of the von Frey hair that was used in Studies 1 and 2. As in Study 2, nonspecific effects of iontophoresis were examined at the different doses administered. Also, the effects of a 6.15 minute naloxone iontophoresis was investigated. However, in this study, an additional 4 minutes or 30 seconds of saline iontophoresis was included in order to equalize the time of iontophoresis at each site so that the specific effect of methadone iontophoresis at the two doses could be compared. Finally, the effect of pretreating the methadone sites with naloxone was compared with sites pretreated with saline iontophoresis. Nonspecific effects of iontophoresis were found for heat pain thresholds and suprathreshold ratings of heat pain, with the saline iontophoresis sites producing greater hyperalgesia to heat pain than control sites. Sites iontophoresed with naloxone produced higher heat pain thresholds than sites iontophoresed with saline, but the effect only approached significance (P=0.056). However, when ratings to 40°C were analyzed separately, naloxone produced significantly less sensitivity to heat than the saline control. This effect was not found for mechanical pressure pain thresholds but a dose effect was obtained, with the 10.15 minute iontophoresis producing significantly lower mechanical pressure pain thresholds than the 6.45 minute iontophoresis. As for the specific effects of methadone, a dose effect was obtained for mechanical pressure pain thresholds, with the longer period of iontophoresis producing greater hyperalgesia. Pretreating methadone sites with naloxone resulted in higher heat pain thresholds. A significant dose effect was also obtained for heat pain thresholds mechanical pressure pain thresholds and sensitivity to heat ratings, with greater hyperalgesia obtained from the total 10.15 minute iontophoresis than the 6.45 minute iontophoresis. Finally, when the results for heat pain thresholds from Study 2 were combined with those from this study; pretreatment of methadone sites with naloxone was found to produce significantly higher heat pain thresholds than pretreatment with saline.
Two experiments were carried out in Study 4 in skin not treated with capsaicin. The first experiment examined whether methadone induced an inflammatory reaction in the skin as a result of iontophoresis. Since the longer duration of iontophoresis produced greater hyperalgesia in Study 3 skin blood flow for a 4 minute iontophoresis was monitored. The effect of methadone iontophoresis on heat and mechanical hyperalgesia was also investigated. The 4 minute methadone iontophoresis produced significantly greater flushing than the saline and control sites, suggesting that methadone provoked the release of histamine. In the second experiment, the effect of pretreating the methadone site with naloxone was compared with pretreatment with saline on skin blood flow and sensory tests. The pressure algometer was replaced by a stronger von Frey hair to measure mechanical hyperalgesia. Although naloxone iontophoresis produced significantly greater vasodilatation than saline, pretreatment with naloxone was found to inhibit the flushing response to methadone compared to pretreatment with saline. The methadone site pretreated with saline also produced significantly lower heat pain threshold than the naloxone pretreated site. However, ratings of heat pain at 45°C produced the opposite effect, that is pretreatment with naloxone produced greater hyperalgesia than pretreatment with saline. No differences were found for mechanical ratings to punctate pressure.
Study 5 was carried out to investigate the effects of repeating a 4 minute iontophoresis in skin not treated with capsaicin. It was hypothesized that the vasodilatation resulting from the methadone iontophoresis in Study 4 was due to histamine release from mast cell degranulation. It was therefore expected that when methadone was iontophoresed for the second time, the degranulated mast cells would be depleted of histamine and other nociceptor inflammatory mediators and methadone would therefore be able to produce analgesia. Overall, methadone produced significantly greater vasodilatation than saline. After the second iontophoresis of methadone, the heat pain threshold was significantly lower at the methadone site than at the saline and control sites. This effect was also obtained for ratings of sensitivity to heat. However, this effect was not detected for sensitivity to punctate pressure.
Study 6 was also carried out in skin not treated with capsaicin. Mepyramine an antihistamine, was used to pretreat the methadone site in the hope that by blocking histamine receptors, analgesia would result from the iontophoresis of methadone. Although pretreatment with mepyramine iontophoresis resulted in higher skin blood flow than saline, nevertheless it significantly inhibited the flushing response to methadone. However, pretreatment with mepyramine did not block the heat and mechanical hyperalgesic effect of methadone. Instead, it increased mechanical hyperalgesia compared with its control site.
The final study was carried out to examine the effects of mepyramine pretreatment on a 4 minute and 30 second methadone iontophoresis in capsaicin-inflamed skin. The mepyramine pretreatment did not produce analgesic effects and neither did it inhibit thermal or mechanical hyperalgesia.
Taken together, the findings of the 8 studies indicate that although peripheral opioid effects were present, as evidenced by naloxone blocking the hyperalgesic effect of morphine and methadone, iontophoresis is not a useful method of introducing opioids into the skin to relieve pain evoked by thermal and mechanical stimuli.
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Bleasdale, Catherine Louise. "The investigation of the role of the vagus nerve and the NTS in the development of mechanical hyperalgesia in a model of immune evoked hyperalgesia." Thesis, University of Bristol, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.402350.
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Nasu, Teruaki, Toru Taguchi, and Kazue Mizumura. "Persistent deep mechanical hyperalgesia induced by repeated cold stress in rats." Elsevier, 2010. http://hdl.handle.net/2237/13012.
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Oh, Jeremy Jaehwan. "Posterior lateral hypothalamus stimulation confirms brain reward site stimulation-induced hyperalgesia." Thesis, Boston University, 2012. https://hdl.handle.net/2144/12548.
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Thesis (M.A.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Pain is known as one of the most important physical sensations that contribute to animal survival. Kornetsky and colleagues (201 0) established mesencephalic reticular formation (MRF) and midbrain forebrain bundle (MFB) thresholds separately and found that simultaneous stimulation of the sites significantly lowered MRF escape thresholds. They also found that the simultaneous stimulation of the sites eliminated the analgesic effect--that is, raising the MRF threshold--of morphine. In an effort to better understand the interaction between rewarding brain stimulation and nociceptive pain, this study expands upon the previous experiment by implanting an electrode in the ventral tegmental area (VTA). However, during the post-mortem histological review, it was found that the rewarding electrodes were implanted in the posterior lateral hypothalamus (PLH), not in the VTA. Our overall results of this experiment demonstrate similar findings as the previous study (Kornetsky et al., 2010). The simultaneous stimulation of the MRF and PLH significantly lowered MRF escape thresholds and eliminated the analgesic effects of morphine. A very low, subthreshold intensity of stimulation to the PLH yielded significantly increased sensitivity to MRF stimulation. Furthermore, the results show that morphine did not lower BSE threshold, when the MRF was simultaneously stimulated with the PLH. An examination of the rewarding electrode placements found in the simultaneous MRF and MFB stimulation experiment by Kornetsky and colleagues (2010) also show rewarding electrode in the PLH, which corroborates with the results in this experiment.
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Dmitrieva, Natalia Ivanovna. "Mechanisms and modulation of visceral pain in an animal model of cystitis." Thesis, King's College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265770.
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Barlas, Panagiotis. "An investigation of the efffects of acupuncture upon experimentally-induced myogenic pain." Thesis, Ulster University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245802.
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Gabra, Bichoy H. "The role of kinin B[indice inférieur 1] receptor in diabetic hyperalgesia." Thèse, Université de Sherbrooke, 2005. http://savoirs.usherbrooke.ca/handle/11143/4207.
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Autoimmune insulin-dependent type 1 diabetes involves an overproduction of cytokines, including interleukin-1[bêta] (IL-1[bêta]) and tumour necrosis factor-[alpha] (TNF-[alpha]), which leads to T-cell-mediated pancreatic [bêta]-cell destruction. It is associated with a series of complications including nephropathy, retinopathy and painful diabetic neuropathy (PDN). Several neurovascular systems are activated in type 1 diabetes including the inducible bradykinin (BK)B[indice inférieur 1] receptor (BKB[indice inférieur 1]-R) subtype which is generally absent or of little impact in healthy states, but highly induced or over-expressed under pathological conditions among which type 1 diabetes, where the over-production of cytokines, the hyperglycemia and the oxidative stress are critical factors for its up-regulation. The present project aimed at studying the development of hyperalgesia in rodent models of type 1 diabetes and characterising the role of the inducible BKB[indice inférieur 1]-R in this diabetic complication, through the use of selective BKB[indice inférieur 1]-R agonists and antagonists. Nociception was evaluated with two types of thermal pain tests; spinal (tail immersion and tail flick tests) and supra-spinal (hot plate and plantar stimulation) tests. Chemically streptozotocin (STZ)-induced diabetic mice and rats showed a marked hyperalgesia that was stable over 4 weeks following the STZ injection. Non-obese diabetic (NOD) and BioBreeding/Worcester (BB/Wor) rats, models of autoimmune spontaneous type 1 diabetes, similarly developed significant hyperalgesia over time (4-32 and 4-24 weeks of age, respectively). Hyperalgesia observed in NOD mice and BB/Wor rats did not correlate with hyperglycemia, but rather preceded the increase in the animal plasma glucose concentration. This finding supports the hypothesis that type 1 diabetic complications start early during the progression of the disease, even before the diagnosis of the state of hyperglycemia. The selective BKB[indice inférieur 1]-R agonist, desArg[indice supérieur 9]BK (DBK), which did not affect nociception in control non-diabetic animals, potentiated hyperalgesia in STZ-diabetic and NOD mice. In addition, the acute and chronic administration of the selective BKB[indice inférieur 1]-R antagonists R-715 and R-954 significantly attenuated diabetic hyperalgesia in all tested animals models. Our results also showed that stimulation of the inducible BKB[indice inférieur 1]-R activates several neurotransmitter systems responsible for the mediation of diabetic hyperalgesia including the substance P (SP), nitric oxide (NO) and calcitonin gene-related peptide (CGRP). Nevertheless, the hyperalgesia observed in wild type diabetic mice was totally absent in the BKB[indice inférieur 1]-R-knockout (KO) diabetic mice in which DBK had no effect on nociceptive responses."--Résumé abrégé par UMI.
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Hay, Catriona Helen. "Injury responses in the spinal cord : gene expression studies." Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244087.
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McClean, Mercedes. "NMDA antagonists as antinociceptive agents." Thesis, University of Bristol, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311427.
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Grimes, Jeffrey Scott. "The impact of a noise stressor on capsaicin-induced primary and secondary hyperalgesia." Thesis, Texas A&M University, 2003. http://hdl.handle.net/1969.1/249.
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In searching for new human pain models that more closely resemble clinical pain states, the capsaicin pain model has emerged as a viable model for both inflammatory and neuropathic pain states. A principal benefit of the capsaicin model is that it allows study of two different pain processes, primary and secondary hyperalgesia. Primary hyperalgesia is characterized by spontaneous pain and both heat and mechanical hyperalgesia. In addition, it is likely the result of activation and sensitization of both peripheral and central nociceptors. In contrast, secondary hyperalgesia is characterized by only mechanical hyperalgesia and is caused by the sensitization of central nociceptive neurons. Previous research utilizing the capsaicin pain model has primarily focused on the neural properties with little focus on the impact of affective states on capsaicin-related pain processes. The present study examined the impact of a noise stressor on both primary and secondary hyperalgesia. Results indicated that the effects of the noise stressor impacted secondary hyperalgesia, but not primary hyperalgesia.
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Btesh, Haratz Joan. "Interaction between TRPV1 and the scaffolding protein AKAP79 and implications for inflammatory hyperalgesia." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608068.
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Rooney, Tessa. "Exploring a Potential Facilitating Role for Pain-Related Attentional Bias in Nocebo Hyperalgesia." Thesis, Faculty of Science, School of Psychology, 2019. https://hdl.handle.net/2123/28533.
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The nocebo effect comprises the negative counterpart of the placebo. This occurs when administration of an inert intervention, coupled with negative information or conditioning, results in the occurrence of negative effects. While the literature agrees on the importance of negative expectancies in activating nocebo effects, other potential factors remain relatively overlooked. The aim of the present study was to use a novel gaze-augmented dot-probe task to investigate whether pain-related attentional bias contributes to nocebo effects. This was founded on theories within the pain literature, which propose a causal role for attentional biases in the subsequent experience of pain. Ninety-three participants (60 female, M = 19.67) were randomly allocated to one of four groups (nocebo-towards, nocebo-away, control-towards, control-away). A gaze-augmented variant of the the dot-probe training task was designed in an attempt to manipulate attentional biases either towards or away from pain. Participants then received either nocebo or control instruction and conditioning, by pairing a sham TENS device with contingently high pain stimulation (nocebo) or non-contingent pairing (control). Participants were required to rate pain intensity, expectancy and distress during a test phase where all TENS and no-TENS shocks were administered at the same intensity. Results showed an overall nocebo effect – rating TENS paired shocks higher than no-TENS – for all outcomes. No consistent training effect was shown for attentional bias across reaction time and eye-tracking measures. However, attentional bias was shown to interact with nocebo conditioning for intensity ratings, with tentative partial support shown for expectancy. The key interaction showed attentional bias condition to differentially affect nocebo extinction trends. Thus, results provide preliminary validation for exploration of attentional bias as a potential mechanism of nocebo hyperalgesia, however necessarily a more sensitive and dependable measure of attentional bias must be established to allow more definitive conclusions.
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Moss, Penny. "Topical menthol identifies cold hyperalgesia in individuals with chronic pain from knee osteoarthritis." Thesis, Curtin University, 2013. http://hdl.handle.net/20.500.11937/1207.
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Chronic pain in knee osteoarthritis may develop as a result of centrally-augmented pain processing. Cold hyperalgesia has been proposed as a key indicator but is problematic to assess. A new topical menthol test was developed. It demonstrated reliability and sensitivity to discriminate between those with normal and abnormal cold pain thresholds in healthy cohorts. In knee osteoarthritis, high menthol test score was associated with greater pain and disability, widespread mechanical hyperalgesia and higher PainDETECT score.
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Myers, Brent. "The role of the amygdala in anxiety-linked visceral hypersensitivity." Oklahoma City : [s.n.], 2010.
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Rondon, Eric Schmidt [UNESP]. "Eficácia anti-hiperalgésica das associações de cetamina e seus isômeros com ifenprodil administradas de forma preventiva e por via subaracnóidea em ratos e cães." Universidade Estadual Paulista (UNESP), 2009. http://hdl.handle.net/11449/101118.
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Em dois ensaios testou-se a eficácia da cetamina e do ifenprodil administrados preventivamente e por via subaracnóidea, no controle da hiperalgesia induzida (p 0,05). As provas farmacológicas utilizaram ratos Wistar em duas etapas: determinação da potência relativa e isobologramas. O estímulo hiperalgésico — injeção intraplantar de prostaglandina E2 - foi avaliado com um analgesímetro digital. Todos fármacos apresentaram ação anti-hiperalgésica com diferentes valores de EC50 crescentes nesta ordem: ifenprodil, cetamina S(+), cetamina racêmica e cetamina R(-). O ifenprodil potencializou a ação da cetamina e seus isômeros e foi potencializado pelo racemato e a forma S(+). Os resultados embasaram os ensaios clínicos. Nestes, oito cães foram utilizados para comparar o efeito anti-hiperalgésico do ifenprodil associado à cetamina racêmica com o uso isolado desta, durante 24 h após lesão cirúrgica incisional no coxim metatársico. Foram avaliados os escores de sedação e de claudicação; contagens da freqüência cardíaca e da respiratória; testes com filamentos de von Frey e medição da superfície de apóio plantar com planímetro nos tempos basal e 60, 90, 120, 180, 240, 480, 720 e 1440 min pós-trauma. A comparação entre grupos e ao longo do tempo revelou que os escores se mantiveram inalterados e as freqüências não variaram significativamente. Os testes de von Frey e com planímetro demonstraram diferenças significativas entre os protocolos. Concluiu-se que, ainda que o estímulo seja cirúrgico, o pré-tratamento com ifenprodil melhora a ação anti-hiperalgésica da cetamina racêmica nas primeiras 24 horas após a lesão.
In two different opportunities, it was tested the efficacy of cetamina and ifenprodil, administered preventively and by spinal route, in the control of induced hyperalgesia (P5 0.05). The pharmacological tests had used Wistar rats in two stages: determination of the relative power and isobolograms. The hyperalgesic stimulus — E2 prostaglandin intraplantar injection — was evaluated by electronic pressure meter. Ali the drugs had presented antihyperalgesic action with different ED50 values increasing in this order: ifenprodil, S(+) ketamine, racemic ketamine and R(-) ketamine. lfenprodil potentiated ketamine and its isomers action, and was potentiated by racemate and S(+) form. fie results had based the clinicai tests. In these, eight dogs had been used to compare the antihyperalgesic effect of ifenprodil associated with ketamine with the isolated use of ketamine during 24 hours after surgicai incision in the metatarsal pad. Sedation and claudication scores, respiratory and cardiac rates, von Frey filaments tests and the determination of plantar support area had been used in baseline and 60, 90, 120, 180, 240, 480, 720 and 1440 min after-trauma. The comparison between groups and throughout the time showed that lhe scores had kept unchanged and the rates had not varied significantly. The tests with von Frey filaments and with planimeter had demonstrated significant differences between the protocols. One concluded that, despite the stimulus is surgical, pretreatment with ifenprodil improves lhe antihyperalgesic action of racemic ketamine in the first 24 hours after the injury.
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Schulte, Helène. "Human experimental pain models : methodological & analgesic studies /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-336-1/.
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SUGIHARA, YASUO, MINORU UEDA, HIDEYUKI NAKASHIMA, KENJIRO NAGAMINE, HISASHI HATTORI, NORIYUKI OZAKI, and KATSUNORI HIRONAKA. "INVOLVEMENT OF GLIAL ACTIVATION IN TRIGEMINAL GANGLION IN A RAT MODEL OF LOWER GINGIVAL CANCER PAIN." Nagoya University School of Medicine, 2014. http://hdl.handle.net/2237/20551.
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Kearns, Austin. "MECHANOSENSITIVE REGULATION OF INFLAMMATORY RESPONSES IN ASTROCYTES: AN UNDERLYING MECHANISM OF OPIOID-INDUCED HYPERALGESIA." OpenSIUC, 2021. https://opensiuc.lib.siu.edu/theses/2814.
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Opioids are gold-standard analgesics for pain relief in chronic pain conditions. Paradoxically, chronic opioid use causes an enhanced pain sensitivity termed ‘Opioid-induced hyperalgesia’ (OIH). OIH is a clinically relevant problem associated with the use of opioids. In addition to decreasing quality of life, increased pain from OIH necessitates increasing dosages of analgesics to effectively control the pain, resulting in an increased risk of opioid epidemics, addiction, and overdose. To prevent this clinically important effect, it is necessary to understand how chronic opioid use causes hyperalgesia. Our preliminary studies revealed that synaptic plasticity in the spinal dorsal horn (SDH) is dependent on neuron type in the OIH model and occurs concurrently with hyperalgesia, suggesting central sensitization as a mechanism of OIH. We found that astrocyte ablation blocked mechanical hyperalgesia and neuron type-dependent synaptic plasticity, indicating that astrocytes are critically involved in OIH. Additionally, morphine treatment upregulated IL-1β expression in the SDH in our preliminary experiments. Inhibition of IL-1β prevented OIH and blocked the repeated morphine-induced synaptic plasticity in the SDH, suggesting IL-1β is a key player in the pathogenesis of OIH. Astrocytes and other glial cells are critical in the development and maintenance of neuroinflammatory conditions, such as OIH, through the release of proinflammatory cytokines (PICs), including IL-1β. The mechanosensitive ion channel, Piezo1, was recently found to be upregulated in astrocytes and microglia under LPS-induced inflammatory conditions, and activation of Piezo1 was found to reduce IL-1β expression in LPS-inflamed primary mouse astrocytes. The goal of this study was to investigate the function of Piezo1 as a potential treatment for neuroinflammatory diseases of the CNS in a model of LPS-induced inflammation. In this study, we created a culture cell model of LPS-induced astrocytic neuroinflammation using the C8-S type II astrocyte culture cell line. We used a multi-disciplinary approach of electrophysiology and imaging to assess changes in calcium flux induced by the selective Piezo1 agonist, Yoda1, and mechanosensitive ion channel activity in the LPS-stimulated C8-S culture astrocytes. We found that calcium flux is increased in LPS stimulation and augmented by additional Yoda1 treatment. We also found that LPS stimulation increases mechanosensitive ion currents and stiffens cell membranes using patch-clamp electrophysiology techniques. These results indicate that Piezo1 is likely upregulated in the LPS model of cultured astrocytes, thus mechanosensitive responses are increased. Results from these experiments reveal key information about the mechanical properties of Piezo1 and poise Piezo1 as a promising therapeutic for OIH and other neuroinflammatory diseases caused by astrocytic IL-1β release.
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Zhang, Xiaojun. "Analgesic effect of paeoniflorin in rats with visceral hyperalgesia induced by neonatal maternal separation." HKBU Institutional Repository, 2008. http://repository.hkbu.edu.hk/etd_ra/919.
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Largent-, Milnes Tally Marie. "NEUROKININ 1 RECEPTORS AND THEIR ROLE IN OPIOID-INDUCED HYPERALGESIA, ANTINOCICEPTIVE TOLERANCE AND REWARD." Diss., The University of Arizona, 2010. http://hdl.handle.net/10150/193763.
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Pain is the most common and debilitating sign of a medical problem, with nearly 15 million patients suffering from chronic pain, including neuropathic pain. Widely used therapies for treating neuropathic pain include tri-cyclic antidepressants, opioids, anticonvulsants, non-steroidal anti-inflammatory agents and combinations thereof. Despite the abundance of treatments, the management of chronic pain remains difficult due to an inability for many patients to achieve appropriate pain relief at doses which are tolerable over long periods of time.Opiates (natural products), or opioids (synthetic derivatives), are considered the gold standard of analgesic care, though with little efficacy for neuropathic pain. Opioids are associated with unwanted side effects, including paradoxical pain and abuse liability that may result from several nervous system adaptations within the pain modulating neural network. These dose related side effects become more prevalent as clinicians try to overcome analgesic tolerance.Molecular mechanisms underlying these unwanted side effects have been studied extensively, and the literature purports a variety of contributing factors and neurobiological adaptations. The studies herein describe additional molecular adaptations and novel pharmacological approaches to counteract these changes. First, the contributions of neurobiological remodeling within a single receptor system (the opioid system) were investigated in the spinal dorsal horn after peripheral nerve ligation and chronic exposure to an opioid agonist in combination with an ultra-low-dose of opioid antagonist. The effects of the ultra-low-dose opioid antagonist naltrexone on the efficacy of oxycodone for neuropathic pain were investigated after both central and systemic administration.Secondly, molecular remodeling occurs across different receptor systems in the pain network, including altered regulation of pronociceptive molecules (e.g. substance P; SP). Previous studies have reported that opioid-induced hyperalgesia, tolerance and reward can be prevented by a blockade or ablation of SP activity at the neurokinin 1 receptor (NK1). We have characterized single compounds, rationally designed to act as opioid agonists and an NK1 antagonist using in vitro assays and the efficacy in vivo using rodent models of pain, antinociceptive tolerance and reward. Collectively, these studies validate the concept of targeting multiple neurobiological adaptations as a therapeutic option for neuropathic pain and reducing opioid- mediated side effects.
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McAllister, Stacy L. "Peripheral neural sprouting contributes to endo-induced vaginal hyperalgesia in a rat model of endometriosis." Thesis, The Florida State University, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=3681750.
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Endometriosis, defined by ectopic growths of uterine tissue, is considered an enigma because it is unknown how or even if these abnormal growths contribute to the painful conditions including dysmenorrhea, dyspareunia, and chronic pelvic pain that often accompany the disease. Many clinicians and biomedical scientists assume that the amount of ectopic growth (cysts) predicts the presence or severity of pain symptoms, even though considerable evidence suggests that this assumption is unwarranted. Studies from our laboratory using a rat model of surgically-induced endometriosis (ENDO) demonstrated for the first time that the cysts develop a sensory and sympathetic nerve supply. This discovery gave rise to the hypothesis that this newly-sprouted innervation of the cysts is a significant contributor to the development (i.e., generation) and maintenance of painful symptoms. One of these common symptoms, studied here, is vaginal hyperalgesia (often called dyspareunia in women). The purpose of this dissertation was to use a combination of immunohistochemical, physiological, and behavioral methods to test various aspects of this hypothesis.
In the first study, the developmental time course of cyst innervation (sensory and sympathetic) and ENDO-induced vaginal hyperalgesia was examined over a 10 week period post-ENDO. It was found that rudimentary innervation appears within the cysts at 2 weeks post-ENDO, and becomes active at 3 weeks post-ENDO. Between 4 and 5 weeks post-ENDO, vaginal hyperalgesia becomes significant, but is highly variable as the innervation increases and approaches maturity. By 8 to 10 weeks post-ENDO the cyst innervation and hyperalgesia have both matured completely, plateaued and stabilized. Based on these findings, the developmental timeline was divided into three phases: INITIAL (1-2 weeks post-ENDO), TRANSITIONAL (4-6 weeks post-ENDO), and ESTABLISHED (8-10 weeks post-ENDO). In each phase, characteristics of the cyst innervation and vaginal hyperalgesia were found to be as follows: INITIAL, no innervation and no vaginal hyperalgesia; TRANSITIONAL, immature but active innervation and significant but highly variable hyperalgesia; ESTABLISHED, mature innervation and stabilized hyperalgesia both of which varied with the estrous cycle.
Then, in each of the three phases, the contribution of the cysts (and their innervation) to ENDO-induced vaginal hyperalgesia was tested, by removing the cysts and assessing the effect on the development and maintenance of the vaginal hyperalgesia. In the TRANSITIONAL phase, the relationship between the severity of ENDO-induced vaginal hyperalgesia and the innervation of the cysts, eutopic uterus, and vaginal canal was also assessed.
The effect of cyst removal on ENDO-induced vaginal hyperalgesia in the INITIAL phase prevented the development of vaginal hyperalgesia. In the TRANSITIONAL phase, cyst removal did not significantly alleviate the vaginal hyperalgesia developed prior to cyst-removal, but, prevented its future development. In the ESTABLISHED phase, cyst removal completely alleviated the vaginal hyperalgesia. Further, in the TRANSITIONAL phase, innervation of the cysts (sensory and sympathetic) and innervation of the vaginal canal (sympathetic only) significantly correlated with severity of ENDO-induced vaginal hyperalgesia.
Overall, results from these studies strongly support the general hypothesis that the innervation of the cysts contributes to ENDO-induced vaginal hyperalgesia. Specifically, the cyst innervation likely contributes to the development , severity, and maintenance of ENDO-vaginal hyperalgesia. Importantly however, the varying effects of cyst removal suggest that mechanisms by which the innervation operates to contribute to the vaginal hyperalgesia change during its progression through the three phases from peripheral sensitization to peripherally-independent then peripherally-dependent, hormonally-modulated central sensitization. Thus changes, which emerge most clearly in the TRANSITIONAL phase, could help explain the poorly-understood, clinically-challenging issue on how pain transitions from an acute to a chronic problem, not only in endometriosis but also in other chronic pain conditions.
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Hsieh, Meng-Tzu. "Spinal processing of A-nociceptor inputs in primary and secondary inflammatory hyperalgesia in the rat." Thesis, University of Bristol, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.681504.
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Hyperalgesia is a symptom of tissue damage and inflammation. In primary hyperalgesia (within the area of injury), there is increased responsiveness to both heat and mechanical stimuli, whereas in secondarY hyperalgesia (outside the area of injury), it is generally reported that responses are only enhanced to mechanical, not heat stimuli. However, recent work from this laboratory has demonstrated that secondary hyperalgesia is A-nociceptor-dependent, rather than being stimulus-modality dependent, explaining the lack of heat but the presence of mechanical hyperalgesia in secondary hyperalgesia. Inflammation leads to changes in the number or affinity of opioid receptors in spinal cord. The segregated expression of delta and mu receptors (DOR & MOR) on A- and C-nociceptors has been recently reported, and is hypothesised to differentially modulate mechanical and thermal nociceptive behaviours respectively. Therefore, the overall aim of work described in this thesis was to investigate how the spinal dorsal horn processes the inputs from different subsets of primary afferent nociceptors in primary and secondary hyperalgesia, and the role of opioid receptors in the regulation of nociceptive processing in the spinal cord. Primary and secondary inflammatOlY hyperalgesia were induced by injection of Freund's Complete Adjuvant into dorsal hindpaw and knee joint respectively. The immediate early gene product Fos was used as a neuronal marker of nociceptive processing in the spinal cord. Using an experimental approach to preferentially activate A- or C-fibre nociceptors, it was found that C-fibre-evoked withdrawal reflexes were facilitated in primary hyperalgesia, whereas A-fibre-evoked withdrawal reflexes were facilitated in secondary hyperalgesia. Additionally, both A- and C-nociceptor stimulations evoked more Fos-like immunoreactivity (FU) in superficial but not deep dorsal horn in the animal model of primary hyperalgesia, whereas FU in response to Abut not C-nociceptor stimulation was increased in the superficial and deep dorsal horn in the animal model of secondary hyperalgesia. Spinal DOR and MOR activation inhibited both C- and A-nociceptor- evoked reflexes in both naives and inflamed animals. The DOR agonist had a greater effect on A-fibre-withdrawal thresholds in secondary hyperalgesia than naives, and a lesser effect on A-fibre-nociception in primary hyperalgesia, suggesting that DOR has a greater contribution to the modulation of A-nociceptor inputs in thermal primary and secondary hyperalgesia than MOR. Spinal DOR activation also had greater anti nociceptive effect on mechanical stimuli than MOR, but these anti nociceptive effects were equivalent in all animals. Spinal MOR activation produced antinociception in mechanical nociception in only secondary hyperalgesia, suggesting the more critical role ofMOR in modulating mechanical pain in secondary hyperalgesia. This study indicates the impOliant role of A-nociceptors in mediating secondary hyperalgesia and the different neuronal mechanisms between primary and secondary hyperalgesia. Such distinctions may be useful in treating clinical syndromes associated with pathophysiological pain.
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Macri, Gabriella. "The effect of proximity to pain on protective blink reflexes in individuals with induced hyperalgesia." Thesis, Macri, Gabriella (2016) The effect of proximity to pain on protective blink reflexes in individuals with induced hyperalgesia. Honours thesis, Murdoch University, 2016. https://researchrepository.murdoch.edu.au/id/eprint/40613/.
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The present study explored the notion that proximity to pain increases protective blink reflexes, and that individuals with chronic pain experience an exacerbation of this effect. Chronic pain sufferers experience a heightened sensitivity to pain (hyperalgesia) and body-space perceptual disturbances. Thus, this study predicted that healthy individuals induced with similar symptoms would have stronger blink reflexes when the stimulated wrist was closer to the face. Adopting a between-subjects design, half of the participants (N = 14) received high-frequency electrical stimulation (HFS) to induce hyperalgesia while the other half of the participants (N = 14) did not. Firstly, participants underwent psychophysical testing on the wrists and forehead to discern baseline sensitivity to stimuli. The HFS condition then completed an electrical detection threshold test to determine the stimulus intensity of the HFS procedure. Following HFS of the wrist, psychophysical testing was repeated to discern changes in sensitivity. Lastly, all twenty-eight participants completed the blink reflex procedure, consisting of a sequence of sixty electrical stimuli applied to the head and the wrist. Independent variables included the position of the wrist (close vs. far), and the site stimulated (head alone, wrist alone, vs. head + wrist together). Dependent variables included pain and sharpness ratings of each stimulus, in addition to the magnitude of the blinks. Results revealed that blink reflexes increased when the wrist was close to the face, confirming the findings of previous literature on proximity to pain. Although the HFS group gave higher sharpness ratings for close stimuli, there was no difference between groups for pain ratings and blinks. Thus, the central premise was not substantiated. Additionally, simultaneous stimulation of the head and the wrist increased all dependent variables; however, this effect did not interact with the proximity effect. Further research should collect a larger sample for more meaningful comparisons between groups.
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Reicherts, Philipp [Verfasser], and Matthias [Gutachter] Wieser. "Cognitive and Emotional Influences on Placebo Analgesia and Nocebo Hyperalgesia / Philipp Reicherts. Gutachter: Matthias Wieser." Würzburg : Universität Würzburg, 2014. http://d-nb.info/1111886865/34.
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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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Melo, Bruna de 1987. "Envolvimento de mediadores inflamatórios na hiperalgesia muscular induzida por contração isométrica sustentada em ratos." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/244474.
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Orientador: Maria Cláudia Gonçalves de Oliveira FusaroDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Aplicadas
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Resumo: Estudos demonstram que a dor muscular induzida por contração isométrica sustentada (CIS) possui importante impacto socioeconômico, no entanto, apesar de sua relevância clínica, os mecanismos inflamatórios envolvidos no desenvolvimento desse tipo de dor ainda são pouco compreendidos. O objetivo deste estudo foi analisar os mecanismos inflamatórios envolvidos no desenvolvimento desse tipo de hiperalgesia muscular. Para isso foi utilizado o modelo de hiperalgesia muscular induzido por contração isométrica sustentada, recentemente desenvolvido por nosso grupo de pesquisa, que consiste na indução de contração muscular isométrica no músculo gastrocnêmio de ratos machos Wistar, pesando entre 200 e 250g, que receberam uma corrente elétrica através do equipamento da marca Grass, modelo SX88R, corrente monofásica, pulso repetido, frequência de 50Hz, duração de pulso de 19ms através de eletrodos tipo agulha, pelo período de 1 hora. Para traçar o perfil inflamatório deste modelo foram administrados via intramuscular, 5 minutos, antes da contração isométrica as seguintes drogas: DALB K (3;30'mu'g) e Bradizida (1,5;15 'mu'g)(antagonistas dos receptores de bradicinina B1 e B2, respectivamente), Atenolol (0,6; 6'mu'g) e ICI 118551(0,15;1,5'mu'g) (antagonistas dos receptores adrenérgicos 'beta'1 e 'beta', respectivamente), Indometacina, uma hora antes (10;100'mu'g) (inibidor não seletivo das cicloxigenases) e A317491 (0,6; 6; 60 'mug) (antagonista seletivo dos receptores P2X3 e P2X2/3); e administrado intraperitoneal, 20 minutos antes, a Fucoidina (25mg/Kg) (inibidora da ação das selectinas). Os resultados demonstraram que todos esses antagonistas e inibidores reduziram significativamente a hiperalgesia muscular induzida pela contração isométrica sustentada, confirmando o envolvimento da bradicinina, aminas simpatomiméticas, prostaglandinas, neutrófilos e do ATP endógeno via receptores P2X3 e P2X2/3 na hiperalgesia muscular induzida pela contração isométrica sustentada. Esses resultados delineiam pela primeira vez o perfil inflamatório da hiperalgesia muscular induzida por contração isométrica sustentada e sugerem importantes alvos terapêuticos para estudo e tratamento da dor muscular, além de abrir novas perspectivas de estudo de outros mecanismos importantes no desenvolvimento da mesma
Abstract: Studies show that muscle pain induced by sustained isometric contraction (CIS) have an important socioeconomic impact, however, despite their clinical relevance, the inflammatory mechanisms involved in the development of this type of pain are still poorly understood. The aim of this study was to analyze the inflammatory mechanisms involved in the development of this type of muscle hyperalgesia. For this model of muscle hyperalgesia induced by sustained isometric contraction, recently developed by our research group, which consists of the induction of isometric muscle contraction in the gastrocnemius muscle of male Wistar rats were used, weighing between 200 and 250g, receiving an electric current through the equipment brand Grass , model SX88R , single phase , repeated pulse frequency of 50 Hz , pulse duration of 19ms via needle-like electrodes for a period of 1 hour. To trace the inflammatory profile of this model, the following drugs were administered intramuscularly 5 minutes before the isometric contraction: DALB K (3; 30'mu'g) and Bradizyde (1.5, 15 mg) (antagonists of bradykinin B1 and B2 receptors, respectively), Atenolol (0.6 ; 6'mu'g) and ICI 118551 (0.15, 1.5 mg) ('beta1 and 'beta'2 adrenergic receptor antagonists, respectively), indomethacin (10 ; 100'mu'g ) ( inhibitory action of cyclooxygenase ) and A317491 ( 0.6 , 6, 60 mg) (selective antagonist of P2X3 and P2X2 / 3 receptors) , and administered intraperitoneally 20 minutes before the fucoidin ( 25mg/Kg ) ( inhibitory action of selectins) . The results showed that all of these antagonists and inhibitors significantly reduced muscular hyperalgesia induced by sustained isometric contraction, confirming the involvement of bradykinin, sympathomimetic amines, prostaglandins, neutrophils and endogenous ATP via P2X3 and P2X2/3 receptors in muscle hyperalgesia induced by isometric contraction sustained. These results delineate first the inflammatory profile of muscle hyperalgesia induced by sustained isometric contraction and suggest important targets for study and treatment of muscle pain, and open new perspectives for the study of other important mechanisms in the development of the same
Mestrado
Biodinâmica do Movimento Humano e Esporte
Mestra em Ciências da Nutrição e do Esporte e Metabolismo
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Rondon, Eric Schmidt. "Eficácia anti-hiperalgésica das associações de cetamina e seus isômeros com ifenprodil administradas de forma preventiva e por via subaracnóidea em ratos e cães /." Jaboticabal : [s.n.], 2009. http://hdl.handle.net/11449/101118.
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Resumo: Em dois ensaios testou-se a eficácia da cetamina e do ifenprodil administrados preventivamente e por via subaracnóidea, no controle da hiperalgesia induzida (p 0,05). As provas farmacológicas utilizaram ratos Wistar em duas etapas: determinação da potência relativa e isobologramas. O estímulo hiperalgésico - injeção intraplantar de prostaglandina E2 - foi avaliado com um analgesímetro digital. Todos fármacos apresentaram ação anti-hiperalgésica com diferentes valores de EC50 crescentes nesta ordem: ifenprodil, cetamina S(+), cetamina racêmica e cetamina R(-). O ifenprodil potencializou a ação da cetamina e seus isômeros e foi potencializado pelo racemato e a forma S(+). Os resultados embasaram os ensaios clínicos. Nestes, oito cães foram utilizados para comparar o efeito anti-hiperalgésico do ifenprodil associado à cetamina racêmica com o uso isolado desta, durante 24 h após lesão cirúrgica incisional no coxim metatársico. Foram avaliados os escores de sedação e de claudicação; contagens da freqüência cardíaca e da respiratória; testes com filamentos de von Frey e medição da superfície de apóio plantar com planímetro nos tempos basal e 60, 90, 120, 180, 240, 480, 720 e 1440 min pós-trauma. A comparação entre grupos e ao longo do tempo revelou que os escores se mantiveram inalterados e as freqüências não variaram significativamente. Os testes de von Frey e com planímetro demonstraram diferenças significativas entre os protocolos. Concluiu-se que, ainda que o estímulo seja cirúrgico, o pré-tratamento com ifenprodil melhora a ação anti-hiperalgésica da cetamina racêmica nas primeiras 24 horas após a lesão.Abstract: In two different opportunities, it was tested the efficacy of cetamina and ifenprodil, administered preventively and by spinal route, in the control of induced hyperalgesia (P5 0.05). The pharmacological tests had used Wistar rats in two stages: determination of the relative power and isobolograms. The hyperalgesic stimulus - E2 prostaglandin intraplantar injection - was evaluated by electronic pressure meter. Ali the drugs had presented antihyperalgesic action with different ED50 values increasing in this order: ifenprodil, S(+) ketamine, racemic ketamine and R(-) ketamine. lfenprodil potentiated ketamine and its isomers action, and was potentiated by racemate and S(+) form. fie results had based the clinicai tests. In these, eight dogs had been used to compare the antihyperalgesic effect of ifenprodil associated with ketamine with the isolated use of ketamine during 24 hours after surgicai incision in the metatarsal pad. Sedation and claudication scores, respiratory and cardiac rates, von Frey filaments tests and the determination of plantar support area had been used in baseline and 60, 90, 120, 180, 240, 480, 720 and 1440 min after-trauma. The comparison between groups and throughout the time showed that lhe scores had kept unchanged and the rates had not varied significantly. The tests with von Frey filaments and with planimeter had demonstrated significant differences between the protocols. One concluded that, despite the stimulus is surgical, pretreatment with ifenprodil improves lhe antihyperalgesic action of racemic ketamine in the first 24 hours after the injury.
Orientador: Carlos Augusto Araújo Valadão
Coorientador: Carlos Amilcar Parada
Banca: Juan Carlos Duque Moreno
Banca: Silvana Lima Górniak
Banca: Stelio Pacca Loureiro Luna
Banca: Antonio de Queiroz Neto
Doutor
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Karam, Marc Christophe. "The role of cytokines in the regulation of hyperalgesia and disease progression in Leishmania major infection." Thesis, University of Surrey, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.431123.
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Rowe, R. K., G. I. Ellis, J. L. Harrison, A. D. Bachstetter, G. F. Corder, Eldik L. J. Van, B. K. Taylor, F. Marti, and J. Lifshitz. "Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge." SAGE Publications, 2016. http://hdl.handle.net/10150/614986.
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Background: Nociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation. Results: To test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an acute time course. In a second cohort, peripheral inflammation was induced seven days after surgery/injury with an intraplantar injection of carrageenan. This was followed by measurement of mechanical hyperalgesia, glial fibrillary acidic protein and Iba1 immunohistochemical analysis of neuroinflammation in the brain, and flow cytometric analysis of T-cell differentiation in mucosal lymph. Traumatic brain injury increased interleukin-6 and chemokine ligand 1 levels in the cortex and serum that peaked within 1-9 h and then resolved. Intraplantar carrageenan produced mechanical hyperalgesia that was potentiated by traumatic brain injury. Further, mucosal T cells from brain-injured mice showed a distinct deficiency in the ability to differentiate into inflammation-suppressing regulatory T cells (Tregs). Conclusions: We conclude that traumatic brain injury increased the inflammatory pain associated with cutaneous inflammation by contributing to systemic immune dysregulation. Regulatory T cells are immune suppressors and failure of T cells to differentiate into regulatory T cells leads to unregulated cytokine production which may contribute to the potentiation of peripheral pain through the excitation of peripheral sensory neurons. In addition, regulatory T cells are identified as a potential target for therapeutic rebalancing of peripheral immune homeostasis to improve functional outcome and decrease the incidence of peripheral inflammatory pain following traumatic brain injury.
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Svensson, Camilla I. (Camilla Ingegerd). "The role of he p38/PLA₂/Cox-2 cascade and microglia in spinal sensitization and hyperalgesia /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2005. http://wwwlib.umi.com/cr/ucsd/fullcit?p3167841.
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CAMERONE, ELEONORA MARIA. "When do placebo and nocebo work? The role of time on placebo analgesia and nocebo hyperalgesia." Doctoral thesis, Università degli studi di Genova, 2021. http://hdl.handle.net/11567/1057902.
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Verbal suggestions are strong modulators of one’s expectations and they can be used to induce placebo and nocebo responses. Research so far has investigated the magnitude (i.e. stronger or weaker) and the direction (i.e. increase or decrease of pain) of verbal suggestions, while no attention has been given to the dimension of time. Relying on three main experiments, which investigated the influence of temporal verbal suggestions in modulating the onset of action of placebo analgesia and nocebo hyperalgesia, this thesis seeks to address this shortcoming.
In Study 1, pain was induced experimentally on healthy participants via short- lasting, medium-to-low intensity electrical stimuli. After each noxious stimulus participants rated their pain from 0 (no pain) to 10 (unbearable pain). Partic- ipants were assigned to one of three placebo groups, three nocebo groups, a no expectancy (NE) group, or a natural history (NH) group. An inert cream was ad- ministered to all participants, except from those in the NH group, while different verbal suggestions were given according to group allocation. Participants in the placebo groups were told that the cream had analgesic properties setting in after 5 (Placebo Group 5, P5), 15 (Placebo Group 15, P15) and 30 (Placebo Group 30, P30) minutes from cream application. Participants in the nocebo groups were told that the cream had hyperalgesic properties setting in after 5 (Nocebo Group 5, N5), 15 (Nocebo Group 15, N15) and 30 (Nocebo Group 30, N30) minutes from cream application. Participants in the NE group were told that the cream only had hydrating properties and that would not influence pain perception, while those in the NH group did not receive the cream and served to control for pain natural fluctuations over time. Participants repeated the pain test at baseline, after 10, 20 and 35 minutes after the cream application. Mixed-method analysis of variance showed a significant interaction between group and time, indicating that pain ratings varied between time-points and between groups. As expected, post hoc comparisons revealed that placebo and nocebo groups began to show a significant change in pain ratings than the NE group at the expected time point but not earlier. Interestingly, once triggered, the analgesic effect remained stable over time, while the hyperalgesic effect increased over time.
In Study 2 and 3, the influence of temporal suggestions on placebo analgesia (Study 2) and nocebo hyperalgesia (Study 3) onset was investigated using a long lasting, high-intensity, tonic pain model, induced with the Cold Pressor Test (CPT). Heart Rate (HR) was measured to assess whether it correlated with placebo analgesia and nocebo hyperalgesia. In Study 2, participants were assigned to one of two placebo groups, or to the No Expectations (NE) group. In Study 3, participants were allocated to one of two nocebo groups, while the control group (NE) was taken from the previous study (Study 2). In this case participants also received an inert cream and those in the placebo groups were told that the cream had analgesic properties that would set in after 5 (placebo 5, P5) and 30 (placebo 30, P30) minutes from its application. Participants in the nocebo groups were told that the cream had hyperalgesic properties setting in after 5 (nocebo 5, P5) and 30 (nocebo 30, N30) minutes from application, while those in the NE group were told that the cream only had hydrating properties. All the participants repeated the CPT at baseline and after 10 and 35 minutes from cream application. Percentage change in exposure time (pain tolerance) from baseline to Test 10 (∆10) and to test 35 (∆35) and changes in HR during CPT were compared between the three groups. In both studies, data were non- parametric and non-parametric statistics were used accordingly. In Study 2, ∆10 was greater in P5 than in NE and P30, indicating analgesia only in the group expecting cream early onset effect. ∆35 was greater in P5 and P30 compared to NE, showing a delayed onset of analgesia in P30 and maintained analgesia in P5. The same results, but in the opposite direction, were reported in Study 3, where hyperalgesia onset followed the temporal verbal suggestions that partici- pants received. HR differences between groups were not significant in Study 2 nor 3.
In conclusion, the experiments demonstrated that both placebo analgesia and nocebo hyperalgesia follow the temporal information provided. In addition, it was shown that once triggered, both placebo analgesia and nocebo hyperalgesia endure over time (at least for the duration of the experimental session). These data apply to experimentally induced pain both of a phasic nature with medium- low intensity and of a tonic nature, reaching high intensities. The important role of verbal suggestions in modulating the onset of action of a given (inert-) intervention could not only aid the clinical use of placebo treatment (e.g., in open-label placebo), but also support the efficacy of active drugs. Indeed, further research is needed to extend these results from healthy participants to patients and from placebos to active interventions.
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Hamlin, Adam Scott. "Functional Neuroanatomy of Morphine-Induced Abstinence, Tolerance, and Sensitisation." University of Sydney, 2006. http://hdl.handle.net/2123/1164.
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Doctor of Philosophy (PhD)The investigation into the relationship between neural plasticity in the rat forebrain associated with opiate-induced behaviours yielded two major results. The major finding of the functional neuroanatomy of acute morphine dependence was that doses of naloxone that induced hyperalgesia following a brief exposure to morphine, in previously drug-naïve rats, caused a specific induction of the inducible transcription factor (itf) proteins c-Fos and zif268 in the extended amygdala. Moreover, doses of naloxone that caused a simple reversal in morphine analgesia failed to induce itf proteins in these same brain regions. This increase in itf proteins was specific to regions of the extended amygdala that receive and process nociceptive information relayed via the spino-parabrachio-amygdaloid pathway and was not observed in other regions that are involved in supraspinal pain modulation such as the rostral ventromedial medulla and the periaqueductal gray. We also found that acute morphine increased c-Fos protein in the basolateral amygdala and the major output nucleus of the central amygdala the medial subdivision. Acute morphine also up-regulated c-Fos protein in striatal, midbrain, and hypothalamic nuclei. A unique finding of the current study was that prolonged exposure to morphine was required to induce c-Fos in these brain regions, as the subsequent administration of naloxone 30-minutes after morphine either reversed or blocked this induction. These results indicate the potential role of the amygdala in analgesia following systemic morphine and in pain facilitation during acute morphine abstinence. Investigation into the neurons and circuitry that undergo long-term neuroplasticity in response to repeated morphine exposure revealed that network-level changes in the distribution of Fos protein in the nucleus accumbens and striatum predicted both tolerance to catalepsy and psychomotor sensitisation. Drug-naïve rats became profoundly cataleptic following morphine, an effect that rats with a drug-history became tolerant. Rats with a history of morphine exposure showed an increase in stereotyped behaviours compared to drug-naïve rats. The major finding of this study was that a shift in the induction of c-Fos protein from a matrix predominance in drug-naïve rats toward a patch predominance in drug-sensitised rats in the accumbens core predicted both tolerance to catalepsy and sensitisation of oral stereotyped behaviours. Acute injection of morphine in a drug-naïve rat induced catalepsy and increased the number of c-Fos-positive neurons in matrix striatopallidal projection neurons of the rostral accumbens core. An increase in activity of striatopallidal projection neurons, which give rise to the indirect pathway, could potentially increase inhibitory drive to the pedunculopontine nucleus (PPN). The PPN, long known as a site of termination for basal ganglia output, is thought to direct the outflow of incentive-motivational and sensorimotor information from the nucleus accumbens to pons, medullary, and spinal cord nuclei translating the incentive impact of the stimuli into appropriate motor, autonomic and emotive responses (Winn et al., 1997). Inhibition of this nucleus would cause the animal to be unable to initiate a movement and in effect lock up, which is precisely what cataleptic postures look like. In contrast c-Fos-positive neurons were decreased in the rostral matrix and increased in patch striatonigral projection neurons along the rostro-caudal extent of the accumbens core when morphine was administered to drug-sensitised rats. Striatonigral neurons located in the patch give rise to the direct pathway innervating the dopaminergic neurons in both substantia pars compacta and the dopamine rich islands in the substantia nigra pars reticulata (Berendse et al., 1992; Gerfen, 1992; Furuta et al., 2002). Activity of this pathway is thought to be involved in the initiation of movement (Gerfen, 1992; Gerfen and Wilson, 1996), however, when this pathway is overstimulated as is the case when morphine is injected in drug-sensitised rats this could potentially cause increased activity of PPN neurons leading to repetitive psychomotor behaviours or stereotypy. This data adds to the growing body of evidence that suggests that long-term neuroadaptations induced by drugs of abuse including morphine that lead to behavioural sensitisation involves the circuitry that includes the nucleus accumbens.