Dissertations / Theses on the topic 'Neuropathic pain'
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Casey, Sherelle. "Cannabinoids for Neuropathic Pain." Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/24007.
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Neuropathic pain is a severe chronic syndrome and is poorly served by current pharmacotherapeutics. There is some evidence that the cannabis constituents tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination relieves neuropathic pain. However, there is little to no animal evidence for their effectiveness and side effects in neuropathic pain models. In this thesis, a systematic analysis of THC and CBD was performed in a mouse neuropathic pain model. Systemic subcutaneous and oral THC had high anti-allodynic efficacy, but was accompanied by side effects. By contrast, CBD had lower anti-allodynic efficacy, but lacked side effects. Isobolographic analysis demonstrated synergistic analgesia for combination THC and CBD for subcutaneous but not oral administration. Thus, combination THC:CBD had a high therapeutic window when delivered subcutaneously but not orally. Finally, both THC and CBD produced high efficacy anti-allodynia without side effects administered via intrathecal or intraplantar injection. The actions of THC were mostly cannabinoid CB1 receptor mediated, while the actions of CBD were not cannabinoid receptor mediated. An in vitro electrophysiological identified potential cannabinoid targets in sensory neurons. Activity at T-type calcium currents, but not other calcium currents or tetrodotoxin-resistant sodium currents, may account for some of the anti-allodynic activity of THC and CBD. Overall, this thesis provides pre-clinical evidence that the phytocannabinoids THC and CBD alone may be useful as an adjunct therapy for treatment of neuropathic pain, and provides insight as to the ideal ratio and differing benefits and challenges of different administration routes. It also provides some insight into the cellular mechanisms of activity of these phytocannabinoids.
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Searle, Robert David. "Acute neuropathic pain following surgery." Thesis, University of Leeds, 2013. http://etheses.whiterose.ac.uk/6321/.
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Chronic neuropathic pain occurring after an operation is a common problem, however little data is available describing the nature or prevalence of acute neuropathic pain following surgery. In this thesis, I explore the measurement scale properties of a commonly used neuropathic pain screening tool, and use this tool to describe the prevalence of acute and chronic neuropathic pain following thoracic surgery. I also explore how best to diagnose acute neuropathic pain with a Delphi survey of expert opinion and confirmatory observational cohort study. The results show that the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) neuropathic pain screening tool demonstrates acceptable fit to the Rasch measurement model in the chronic postoperative pain population, but only has reliability consistent with use at a group level. Using this tool, I demonstrate that 8% of thoracic surgery patients experience acute neuropathic pain an average of 3 days after surgery, with 22% developing neuropathic pain by 3 months. Experiencing acute neuropathic pain significantly increased the odds of developing chronic neuropathic pain (odds ratio 7.7 [95% confidence interval 1.5-39.7]). A Delphi survey of specialists identified 9 items considered important in the diagnosis of acute neuropathic pain, and suggests that unlike diagnosis in the chronic pain population, a poor response to opioid medications was an important indicator of neuropathic pain. Preliminary results from a matched cohort study confirm this, by demonstrating that verbal descriptors of neuropathic pain are significantly more common in patients with poorly controlled postoperative pain despite strong opioid use.
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Chan, A. W. "Neuropathic pain in diabetes mellitus." Thesis, Cardiff University, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.496046.
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Turcotte, Dana. "Multiple sclerosis-induced neuropathic pain." The Consultant Pharmacist, 2004. http://hdl.handle.net/1993/23316.
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Neuropathic pain (NPP) is a chronic syndrome suffered by patients with multiple sclerosis (MS), for which there is no cure. Underlying cellular mechanisms involved in its pathogenesis are multifaceted, resulting in significant challenges in its management. In addition to its complex pathophysiology, the clinical management of MS-induced NPP is further complicated by the lack of clinical therapeutics trials specific to this population. The primary aim of the work underlying this thesis was to contribute to the evidence-based management of individuals with MS-induced NPP through the completion of two clinical therapeutics trials in this population. A secondary aim was to describe pain variability in this patient population through the development and validation of a pain variability algorithm tool. Resulting from this work, we demonstrated that nabilone – a synthetic oral cannabinoid – represents an effective, well-tolerated and novel treatment for MS-induced NPP. Additionally, we show that the SSRI paroxetine was poorly tolerated in our patient population, with a correspondingly high attrition rate. As a result, we were unable to determine any treatment effect in this trial due to insufficient recruitment due to drop-out. Lastly, we were able to define and describe pain instability in this cohort, noting that approximately 30% of individuals with MS-induced NPP experiencing highly variable daily pain. The results of these projects provide novel information for this patient population. Patients currently living with the daily burden of MS-induced NPP would benefit from additional trials ensuing from this, and other, research in order to initiate a momentum for much-needed clinical research in this complicated patient cohort.
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López, Álvarez Víctor Manuel. "Activity-dependent treatments for neuropathic pain." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/457957.
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El inicio y el mantenimiento del dolor neuropático después de una lesión de nervio periférico implica muchos mecanismos tales como cambios en la transducción, sensibilización central o periférica y numerosos cambios plásticos a nivel central. Los tratamientos farmacológicos habituales no son suficientes para aliviar los efectos de la hiperalgesia o alodinia producida por el dolor neuropático. Es por ello que en esta tesis se estudian dos tratamientos dependientes de actividad como son el ejercicio en cinta rodante y la estimulación eléctrica para observar los efectos hipoalgésicos obtenidos y los mecanismos moleculares implicados en estos beneficiosos cambios.
En los dos primeros capítulos de esta tesis se muestra un nuevo protocolo de ejercicio en cinta rodante en el que aumentamos la velocidad progresivamente durante una hora (iTR). Se ha demostrado que otros protocolos de cinta rodante mejoran la recuperación funcional después de una lesión del sistema nervioso periférico, pero dependiendo de la intensidad y la duración, se han descrito diferentes efectos. En el primer capítulo, utilizando un modelo experimental de dolor neuropático consistente en la sección y reparación del nervio ciático en una rata (SNTR), se encontró que el protocolo de iTR reduce la hiperalgesia por recodificación neural espontánea, reducción de niveles de neurotrofinas para contrarrestar la reinervación colateral nociceptiva, prevención de la disrupción de cotransportadores de cloruro como NKCC1 y KCC2 para mantener la inhibición central y por contrarresto de la reactividad microglial en áreas centrales. iTR también redujo positivamente la hiperalgesia en el área ciática lateral, demostrando que el efecto hipoalgésico de iTR no se limita exclusivamente al bloqueo de la reinervación colateral nociceptiva en la periferia. Los cambios en los circuitos sensoriales centrales también son importantes. Es por ello que en el segundo capítulo encontramos que el iTR también aumentó la actividad de las proyecciones serotonérgicas y noradrenérgicas desde los centros del tronco encefálico restaurando parcialmente la desinhibición central inducida después de la lesión del nervio.
En el tercer capítulo de esta tesis, evaluamos el uso de la estimulación nerviosa periférica (PNS) como tratamiento pasivo dependiente de actividad para el dolor neuropático. El resultado terapéutico junto con el patrón de activación del nervio periférico, están estrechamente relacionados con las diferencias en el tipo y ubicación del electrodo y la intensidad o frecuencia de estimulación. Para ello evaluamos dos modelos experimentales diferentes como candidatos. El modelo de lesión de nervio intacto (SNI) fue la elección inicial, pero la estimulación electrica tuvo efectos muy discretos en la reducción de la hiperalgesia mecánica en comparación con el modelo SNTR. En un trabajo preliminar, se discernió la frecuencia de estimulación que produjese la mejor reducción de la hiperalgesia con estimulación aguda después de la lesión. Posteriormente, mejoramos el tipo de electrodo y la ubicación de éste mediante el diseño de un sistema para hacer estimulación crónica. Se presentaron algunos resultados para los protocolos agudos y repetitivos de estimulación aguda y crónica pero el mejor protocolo de estimulación para reducir la hiperalgesia mecánica fue el protocolo iCES. De forma similar a iTR, iCES consiste en un patrón de estimulación de frecuencia creciente. Se encontró que iCES desencadena una serie de cambios a nivel central, como la restauración de la expresión de KCC2 y el receptor β2 que actúan directamente sobre el aumento de la liberación de GABA en la médula espinal facilitando junto con la disminución de la actividad microglial y astrocitaria, la reducción de hiperalgesia mecánica producida después de SNTR.The onset and maintenance of neuropathic pain following a peripheral nerve injury involves many mechanisms such as changes in transduction, central or peripheral sensitization, and numerous plastic changes at the central level. Usual pharmacological treatments are not sufficient to alleviate the effects of hyperalgesia or allodynia produced by neuropathic pain. Therefore, in this thesis two activity-dependent treatments such as treadmill exercise and electrical stimulation are studied to observe the hypoalgesic effects produced and the molecular mechanisms involved in these beneficial changes. In the first two chapters of this thesis a novel protocol of treadmill exercise is shown, by increasing the velocity progressively during one hour (iTR). It has been shown that other protocols of treadmill ameliorate functional recovery after peripheral nervous system injury but, depending on intensity and duration, different effects have been described. In the first chapter, using an experimental model of neuropathic pain consisting in the section and repair of the sciatic nerve in a rat (SNTR), we found that iTR protocol reduces hyperalgesia by recoding of spontaneous neural activity, reducing neurotrophins levels to counteract nociceptive collateral sprouting, preventing the disruption of chloride cotransporters like NKCC1 and KCC2 to maintain central inhibition and counteracting microglial reactivity at central areas. iTR also positively reduced hyperalgesia in the lateral sciatic area demonstrating that the iTR hypoalgesic effect is not exclusively limited to the blockade of collateral sprouting in the periphery. Changes at central sensory circuits are also important. At the second chapter we found that iTR also increased the activity of serotonergic and noradrenergic projections from brainstem centers partially restoring the central disinhibition induced after the nerve injury. In the third chapter of this thesis, we evaluate the use of peripheral nerve stimulation (PNS) as a passive activity-dependent treatment for neuropathic pain. The therapeutic outcome together with the pattern of peripheral nerve activation, are closely related to the differences in the type and location of electrode, intensity and frequency of stimulation. For this purpose we evaluated two different experimental models as candidates. The spared nerve injury model (SNI) was the initial choice but PNS had very discrete effects in the reduction of mechanical hyperalgesia compared to SNTR. In a preliminary work, we discerned the frequency of stimulation producing the better reduction of hyperalgesia with acute stimulation after injury. Then, we improved the type of electrode and location by designing a system to make chronic stimulation available. We show some results for acute, repetitive acute and chronic stimulation protocols but the best stimulation protocol in reducing mechanical hyperalgesia was iCES protocol. Similarly to iTR, iCES consists of an increasing-frequency pattern of stimulation. We found that iCES triggers a series of changes at central levels, such as the restoration of expression of KCC2 and β2 receptor that act directly on the increase of GABA release in spinal cord facilitating together with the decrease of microglial and astrocytic reactivity, the reduction of mechanical hyperalgesia produced after SNTR.
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Wallace, Victoria C. J. "Peripheral nerve demyelination and neuropathic pain." Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/27605.
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Chronic neuropathic pain, characterised by allodynia (perception of innocuous stimuli as painful) and hyperalgesia (facilitated responses to painful stimuli), is poorly understood and is usually resistant to classical analgesics. Such abnormal pain phenomena can be associated with human demyelinating conditions such as Charcot-Marie-Tooth disease. Using mouse models of peripheral nerve demyelination, we have provided evidence for the consequent establishment of neuropathic pain and investigated possible underlying mechanisms. The first model investigated was the Prx-null mouse. The murine periaxin gene (Prx) is expressed in Schwann cells and encodes L- and S-periaxin, two abundant PDZ-domain proteins thought to have a role in stabilisation of myelin in the peripheral nervous system (PNS). Prx-null mice show progressive demyelination in peripheral nerves and electrophysiological investigations indicate the presence of spontaneous action potential discharge; abnormal activity thought to be critical for the development of persistent pain states. Consistent with the time course of demyelination, Rrx-null mice display an increased behavioural reflex sensitivity to cutaneous mechanical and noxious thermal stimulation. To further investigate the link between demyelination of peripheral nerves and neuropathic pain, we have also characterised a novel model of focal peripheral nerve demyelinating neuropathy. Focal demyelination of the sciatic or saphenous nerve was induced with lysolecithin (lysophosphatidylcholine) and resulted in an increased behavioural reflex sensitivity to both thermal and mechanical tests, peaking at 9-14 days following treatment. Nerve morphology was investigated using light and electron microscopy, which revealed 30-40% demyelination of the treated nerve, (without lysolecithin-treated axon loss) coinciding with peak behavioural changes. Changes in the excitability of saphenous nerves were revealed, with spontaneous action potential discharge of 2-3 impulses per second present at peak behavioural change. No associated change in peripheral activation thresholds or conduction velocity was observed. In both models, immunohistochemical investigations revealed no cell loss in the dorsal root ganglia (DRG) and no evidence for axonal damage. Similar methods revealed changes in the expression of neuropeptide Y, and the sodium channels Nav1.3 and Nav1.8 in DRG neurones. Such changes may account for increased nerve excitability and are known to occur in other models of nerve injury. However, these changes in the demyelinating models occur in a more restricted manner, specifically in the cells of formerly myelinated fibres. Intrathecal injections of the selective NMDA receptor antagonist, [R]-CPP, indicated that NMDA receptor-dependent changes are crucial for the development of a neuropathic pain-like state following peripheral nerve demyelination. Intrathecal administration of pharmacological agents indicated a role for the transcription factor NFkB in the production of the behavioural reflex sensitivity of lysolecithin-treated mice, as well as identifying the endogenous cannabinoid system as an effective inhibitory regulator and potential analgesic target. This study describes the first mouse models of peripheral nerve demyelination designed for the study of neuropathic pain and reveals phenotypic changes in DRG, which may contribute to the development of a neuropathic pain-like state. Therefore, these models may be useful for the evaluation of novel therapeutic targets for the treatment of demyelination-associated neuropathic pain.
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Taylor, Anna. "Peripheral mechanisms of trigeminal neuropathic pain." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=97105.
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Trigeminal neuropathic pain is a unique type of neuropathic pain resulting from damage to primary afferents of the trigeminal nerve that innervates the head and neck region. It is characterized by intractable, unremitting pain in the absence of any overt tissue damage, and represents a significant clinical and societal burden. A thorough understanding of the mechanisms driving this condition is required to adequately treat, and ideally cure, this condition. The skin of the lower lip is innervated by several classes of primary afferents, including myelinated Aβ fibers, thinly myelinated Aδ fibers, and unmyelinated C fibers, which together are able to transduce the variety of innocuous and noxious stimuli encountered in the environment. Nociceptive stimuli are largely mediated by the unmyelinated C fibers, which have been further divided into 2 groups based on neurochemical and anatomical criteria, called the peptidergic and non-peptidergic C fibers. Given that nerve lesions initiating neuropathic pain conditions most often occur in the periphery, changes in the peripheral nervous system following nerve injury are particularly relevant in driving this aberrant pain condition. Therefore, the overall objective of this thesis is to explore the peripheral changes in an animal model of trigeminal neuropathic pain. The results of this thesis are presented in three chapters. The pattern of innervation of non-peptidergic C fibers in the skin of uninjured rats has been described, as well as how this fiber population changes following nerve injury. Concomitant ectopic autonomic fibers were observed in close apposition to the regenerating sensory fibers, and correlated with the behavioral phenotype of the animals. GDNF levels in the skin rapidly increased following nerve injury, and provided a possible mechanism for the ectopic parasympathetic fibers and regenerating non-peptidergic C fibers. Ablation of the non-peptidergic C fibers led to specific sprouting of parasympathetic fibers, but no change in behavior, however ablation of non-peptidergic fibers in neuropathic animals led to an exacerbated pain response. These results suggest an important role for non-peptidergic fibers and autonomic sprouting in neuropathic pain, and identifies GDNF as a potential factor for mediating these changes.La douleur trigeminale neuropathique est une forme unique de douleur qui résulte d'un dommage aux afférents primaires du nerf trijumeau innervant la région de la tête et du coup. Cette douleur constante qui se manifeste en l'absence d'un dommage aux tissus périphériques représente un fardeau social et économique important. Une compréhension rigoureuse des mécanismes qui mènent à cette condition sera nécessaire pour mieux la traiter et préférablement la guérir.La peau de la lèvre inferieure est innervée par des afférents primaires appartenant à différentes classes, incluant les fibres myélinisées Aβ, les fibres légèrement myélinisées Aδ, ainsi que les fibres C non myélinisées. Ensemble, ces fibres peuvent transmettre une variété de stimuli nociceptifs ou inoffensifs tels que rencontrés dans l'environnement. Les stimuli nociceptifs sont majoritairement transmis par les fibres C non myélinisées, lesquelles peuvent être divisées en 2 catégories, peptidergiques ou non peptidergiques, selon des critères neurochimiques et anatomiques. Puisque les lésions nerveuses qui déclenchent la douleur neuropathique se produisent le plus souvent en périphérie, les changements au niveau du système nerveux périphérique sont centraux au développement de la condition douloureuse. Ceci étant dit, l'objectif général de cette thèse est d'explorer les changements périphériques qui se produisent dans un model animal de douleur trigeminale neuropathique.Les résultats de cette thèse sont présentés dans trois chapitres. L'innervation de la peau par les fibres C non peptidergiques chez le rat normal a d'abord été décrite. Ensuite, les changements subis par cette population suivant un dommage au nerf ont été documentés. Suite à un dommage nerveux périphérique, des fibres autonomiques ectopiques ont été observées en proximité des fibres sensorielles en régénération, et ce changement corrélait temporellement avec le phénotype comportemental des animaux. Les niveaux cutanés de GDNF ont rapidement augmenté après le dommage nerveux, fournissant un mécanisme potentiel permettant la régénération des fibres C non peptidergiques et la migration ectopique des fibres parasympathiques. L'ablation des fibres C non peptidergiques a déclenché la pousse des fibres parasympathiques sans changer le comportement des animaux. Par contre, l'ablation de ces fibres chez des animaux neuropathiques a exacerbé la réponse douloureuse de ceux-ci.Ces résultats suggèrent une participation importante des fibres C non peptidergiques et de la migration autonomique dans la douleur neuropathique. De plus, GDNF est rapporté comme étant un facteur pouvant produire ces changements.
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Hutton, E. J. "The skin as a window on mechanisms of neuropathy and neuropathic pain." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1532903/.
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Neuropathies are common, yet the pathogenic mechanisms of many remain incompletely understood. Animal and cell models have provided much useful information about disease mechanisms, and yet translation of this knowledge to clinical practice and disease therapies is often disappointing. One of the difficulties in studying human nerves is limited availability of tissue, due to the morbidity of peripheral nerve (usually sural nerve) biopsy. I sought to evaluate the utility of cutaneous nerves, both generally as a tool to assess the relevance of pathogenic mechanisms identified in animal studies in human disease, and also specifically in evaluating whether immune changes in the skin may play a role in the development of neuropathic pain. Animal models have suggested that proinflammatory cytokines exert algesic effects on nerves, whilst anti-inflammatory cytokines have a counter-regulatory analgesic effect (Üçeyler et al., 2009). More recently, support for a link between variability in systemic and / or local cytokine balance and pain in neuropathy has begun to emerge (Üçeyler et al., 2007c, Üçeyler et al., 2010). Despite some support for a link between painful neuropathies and increased inflammatory and / or decreased antiinflammatory cytokines, it remains unclear whether the immune changes reflect underlying neuropathological processes, a response to nociceptor activation, variability in individual immune response to nerve damage or are a biomarker of another factor indirectly modulating both pain and immune function. It is also unclear whether immune-nerve interactions are unidirectional or bidirectional: does increased nociceptor firing modulate local immune function or does immune response to nerve damage modulate activity of remaining undamaged fibres, or is there a combination of these factors? I sought to understand the effect of acute nociceptor activation on skin immune profile, as well as whether changes in chronic neuropathy would be associated with the presence and intensity of pain.
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Liu, Xue Jun. "Peripheral regulation of inflammatory pain and neuropathic pain by adenosine." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/NQ66636.pdf.
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Bennett, Michael I. "The development of a pain scale for identifying neuropathic pain." Thesis, University of Birmingham, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487879.
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Murai, Nobuhito. "Studies on the analgesic effect of (+)-indeloxazine on neuropathic pain." Kyoto University, 2014. http://hdl.handle.net/2433/193548.
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Fjell, Hjelmström Jenny. "Tetrodotoxin-resistant sodium channels in neuropathic pain /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4181-5/.
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Bennett, Michael I., Nadine Attal, Miroslav M. Backonja, Ralf Baron, Didier Bouhassira, Rainer Freynhagen, Joachim Scholz, Thomas R. Tölle, Hans-Ulrich Wittchen, and Troels Staehelin Jensen. "Using screening tools to identify neuropathic pain." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-112626.
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It is widely accepted that the unique painful and non-painful sensations in neuropathic pain are the result of particular mechanisms, and that specific management strategies for neuropathic pain should be applied to tackle them. Ideally, the treatment of chronic pain should be directed at eliminating the cause of pain, but in reality this is rarely possible. The management of chronic pain is therefore often limited to reducing the intensity of such pain and associated symptoms.
Pain is essentially a subjective phenomenon described with patient-specific symptoms and expressed with a certain intensity. It therefore makes sense to examine the value of verbal descriptors and pain qualities as a basis for distinguishing neuropathic pain from other types of chronic pain. Work by Dubuisson and Melzack (1976) and later by Boureau et al. (1990) supported anecdotal opinion that key words might be discriminatory for neuropathic pain. In the last 5 years, much research has been undertaken to develop screening tools for this purpose. These tools are based on verbal pain description with, or without, limited bedside testing. This paper reviews the strengths and weaknesses of such tools.
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Lowe, Andrew Sheridan. "Functional magnetic resonance imaging of neuropathic pain." Thesis, King's College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419854.
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Bennett, Michael I., Nadine Attal, Miroslav M. Backonja, Ralf Baron, Didier Bouhassira, Rainer Freynhagen, Joachim Scholz, Thomas R. Tölle, Hans-Ulrich Wittchen, and Troels Staehelin Jensen. "Using screening tools to identify neuropathic pain." Technische Universität Dresden, 2007. https://tud.qucosa.de/id/qucosa%3A26855.
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It is widely accepted that the unique painful and non-painful sensations in neuropathic pain are the result of particular mechanisms, and that specific management strategies for neuropathic pain should be applied to tackle them. Ideally, the treatment of chronic pain should be directed at eliminating the cause of pain, but in reality this is rarely possible. The management of chronic pain is therefore often limited to reducing the intensity of such pain and associated symptoms.
Pain is essentially a subjective phenomenon described with patient-specific symptoms and expressed with a certain intensity. It therefore makes sense to examine the value of verbal descriptors and pain qualities as a basis for distinguishing neuropathic pain from other types of chronic pain. Work by Dubuisson and Melzack (1976) and later by Boureau et al. (1990) supported anecdotal opinion that key words might be discriminatory for neuropathic pain. In the last 5 years, much research has been undertaken to develop screening tools for this purpose. These tools are based on verbal pain description with, or without, limited bedside testing. This paper reviews the strengths and weaknesses of such tools.
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Natale, Claudia. "Spinal glycinergic neurotransmission in neuropathic pain models." Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/25376.
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Disruption to inhibitory neurotransmission is commonly associated with the development of chronic neuropathic pain. However, exactly which aspect of inhibition is affected varies between studies with little consensus on the major contributors. I hypothesised that the different neuropathic pain models used in each study contribute to these discrepancies. Thus, the first part of this thesis focused on the following question: Do different neuropathic pain models produce different physiological changes in the spinal cord dorsal horn?
Neuropathic pain is poorly treated with existing analgesics, making the need for novel therapeutics paramount. The glycine transporter 2 (GlyT2) is expressed at inhibitory glycinergic synapses in the spinal cord and novel analgesic compounds targeting it have been developed. The second part of this thesis investigated the cellular actions of one of these novel compounds and asked; How does the novel GlyT2 inhibitor, Oleoyl-D-Lysine, effect glycinergic neurotransmission in the spinal cord dorsal horn?
Patch-clamp electrophysiology was used in both projects. In project 1, changes to glycinergic neurotransmission were investigated in chronic constriction injury (CCI) or partial nerve ligation (PNL) models. Both produced similar behavioural outcomes, but vastly different physiological changes. Reduced glycinergic neurotransmission was observed in the PNL model, but not the CCI model. In project 2, Oleoyl-D-Lysine displayed a minor effect on synaptic glycinergic currents, but its predominant effect was on tonic glycinergic currents and produced no detrimental effects on presynaptic glycine supply.
Overall, these results suggest that each neuropathic pain model should be considered unique and more research should look into the distinct nociceptive circuits involved for a better understanding of neuropathic pain physiology, as well as to identify more novel therapeutic targets. In addition, the findings suggest that despite Oleoyl-D-Lysine’s glycinergic specific mechanism, it may be effective in treating neuropathic pain caused by different injuries because its main effect is to reduce the excitability of the system not just to enhance glycinergic neurotransmission as was previously hypothesised.
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Tam, Denise June. "Role of Glycinergic Neurotransmission in Neuropathic Pain." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/16314.
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The Gate Control Theory of Pain highlights an interconnected network of myelinated and unmyelinated fibres within the dorsal horn (Melzack & Wall, 1965). Currently there are a number of proposed theories to explain the mechanism by which pain is developed, one of which is the theory of disinhibition whereby a reduction of inhibitory neurotransmission leads to over-excitation within the central nervous system (Guo & Hu, 2014; Zeilhofer, 2005). Evidence within my supervisor’s laboratory has identified glycinergic inhibitory neurotransmission to be a key component in the development of neuropathic pain. This study aimed to identify the main reasons for these reductions in inhibitory neurotransmission shown within lamina II of the dorsal horn. It is hypothesised that inhibitory neurotransmission is lost following injury leading to over-excitation within the dorsal horn. The experiments performed within this study were optimised through following vigorous testing procedures often requiring multiple trial and error attempts prior to the development of both valid and reliable results. PKCγ immunoreactive neurons are found within lamina II of the dorsal horn are classified into distinct morphological categories, and are involved in the filtering of nociceptive and mechanical input (Martin, Liu, Wang, Malmberg & Basbaum, 1999). This study showed distinct changes of PKCγ immunoreactive neurons following a neuropathic pain injury suggestive of the possibility of changes to the neural circuitry within the dorsal horn. Furthermore GAD67 neurons in lamina II of the dorsal horn was analysed to identify whether this can be used as a method of identifying changes in presynaptic neurons following neuropathic injury but failed to yield significant results. In conclusion immunohistological studies are found to be limited in providing physiological information on neurons within the dorsal horn. As a result future experimentations seeking alternative techniques must be sought to confirm the significance the results in the study.
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Tang, Qingbo. "Nonopioid actions of dynorphin and neuropathic pain." Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/289125.
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The hypothesis of this dissertation is that peripheral nerve injury will elevate dynorphin in the spinal cord, which has a facilitating effect on the nociceptive pathway via a non-opioid mechanism. Two major questions are addressed in this dissertation: how dynorphin is up regulated, and how dynorphin produces a facilitating effect on the nociceptive pathway. The first question was approached by examining the activation of NF-κB, AP-1, CREB, and MAP kinase pathways following nerve injury. These experiments indicate that there was an increase in the activation of NF-κB, AP-1 and CREB. While it was not known whether the increase in AP-1 and NF-κB activity was occurring in dynorphin-expressing cells, phospho-CREB-ir did not colocalize with prodynorphin. Thus CREB may not play a direct role in dynorphin gene expression. Following nerve injury, there was an increase in phospho-ERK1/2, which was also seen in dynorphin-expressing cells. It is possible that the activation of ERK1/2 may contribute to the up-regulation of dynorphin in some dynorphin-expressing cells. There was also a dramatic increase in phosopho-p38-ir. However, it did not colocalize with prodynorphin. In summary, these experiments indicated that there are profound changes in the cellular signaling pathways following nerve injury, which may play an important role in initiating neuroplastic changes in the spinal cord, including the up-regulation of dynorphin. There is considerable evidence suggesting the involvement of NMDA receptors in the excitatory effect of dynorphin in vivo and possible interaction between dynorphin and NMDA receptors. The interaction between dynorphin and NMDA receptors was further investigated by radioligand binding assay using iodinated dynorphin A(2-17). These experiments suggest dynorphin binds to NMDA receptors with relatively high affinity. Dynorphin appears to interact preferentially with the closed state of NMDA receptors, and may be inhibitory on NMDA receptors. To look for mechanisms which may underlie the excitatory effect of dynorphin, I examined its effect on intracellular calcium level ([Ca²⁺]ᵢ). These experiments suggest that dynorphin A(2-17) elicited an increase in [Ca²⁺]ᵢ in the cortical neurons via a non-NMDA, non-opioid mechanism. This novel action of dynorphin could provide a potential mechanism for the excitatory actions of dynorphin in vivo.
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Gardell, Shannon. "The contribution of descending pain facilitation to the maintenance of neuropathic pain." Diss., The University of Arizona, 2003. http://hdl.handle.net/10150/289935.
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This dissertation will examine the likelihood that tonic activation of descending facilitatory pathways may underlie chronic pain states arising from injuries to peripheral nerves, and that this activation is what maintains neuropathic pain. Activation of these pathways might be the result of plasticity in the RVM that is driven, in part, by release of CCK in response to pain signals from the injured nerve. Hyperactivity of facilitatory ON cells in the RVM may contribute to neuropathic pain and lesions of these cells via the targeted toxin, DERM-SAP, may prevent or reverse neuropathic pain states in the injured animal. Rats treated with DERM or SAP and undergoing SNL exhibited tactile and thermal hypersensitivity. Rats receiving DERM-SAP showed similar responses to sham-operated controls. Administration of RVM DERM-SAP to SNL rats fully reversed established allodynia/hyperalgesia by day 14. Thus, the targeted loss of cells expressing the MOR both prevents and reverses SNL-induced neuropathic pain. Acutely, RVM lidocaine blocked tactile and thermal hypersensitivity on day 6 out to day 12 after SNL, but not on day 3. DERM-SAP pretreatment and DLF lesions did not prevent the onset of tactile and thermal hypersensitivity, but these neuropathic pain signs reversed toward baseline levels beginning on day 4 after SNL. These findings differentiate the mechanisms that initiate neuropathic pain as being independent of supraspinal influences needed to maintain such pain. These descending influences may underlie some of the SNL-induced changes at the spinal level, such as the upregulation of dynorphin and may be key to the maintenance of neuropathic pain. Administration of RVM CCK produces hypersensitivity in naive rats. Pretreatment with RVM DERM-SAP completely blocks the ability of RVM CCK to produce hypersensitivity. These results suggest that the action of CCK in the RVM may be mediated by activation of MOR expressing cells. Enhanced release of CCK in the RVM or upregulation of CCK receptors in RVM neurons after SNL may represent a mechanism of descending pain facilitation to maintain chronic pain states. An observed loss of both MOR and CCK2 receptors after DERM-SAP treatment gives support to the notion that both receptor types may be co-expressed in RVM neurons, and these neurons may be critical for descending facilitatory input from the RVM to maintain neuropathic pain. Understanding the mechanisms of descending facilitation and the spinal effects of, CCK-activated discharge could provide new insight into the modulation of chronic pain, and, furthermore, provide new targets for the development of novel drug therapies.
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Saeed, Abeer Wael. "Chronic neuropathic pain and spinal dorsal horn plasticity." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110356.
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Chronic pain is a debilitating disease with a very important socio-economic burden. The objective of this thesis was to contribute to our understanding of the normal organization of the dorsal horn of the spinal cord and its changes in chronic neuropathic pain, a form of chronic pain that sometimes follows lesions of the nervous system. Our studies focused on two important components of spinal cord pain-related circuitry, the projection neurons and their innervation by the small diameter nociceptive afferents. Spinal lamina I projection neurons have been classified, based on their morphology into fusiform, multipolar and pyramidal neurons. The two former types have been shown to respond to noxious stimuli and express the substance P receptor (NK-1r), while pyramidal neurons seldom express the NK-1r and respond to innocuous cooling only. The two main populations of small diameter nociceptive afferents are the peptidergic, which expresses the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP), and the non-peptidergic, which is mostly devoid of neuropeptides but binds the plan lectin IB4. In the first experimental chapter, we investigated the changes that occur at the level of the spinal dorsal horn in an animal model of chronic neuropathic pain. We demonstrated a de novo expression of NK-1r by pyramidal neurons, similar to that previously observed in our laboratory in a chronic arthritis model. This phenotypic switch was associated with a dramatic increase in the peptidergic (SP-immunoreactive) innervation of this cell population, which normally is sparsely innervated by these fibers. To assess whether pyramidal neurons responded to noxious stimuli in neuropathic animals, we injected capsaicin in the hind paw, which induced a massive internalization of NK-1r on these neurons, an indication of cell activation. To assess whether a chronic pain state was needed to trigger the expression of NK-1r by pyramidal neurons, in the second experimental chapter of this thesis we used a model in which there is no chronic pain but in which previous work from our laboratory had revealed a marked increase in NK-1r in the dorsal horn. In this model, the non-peptidergic population of nociceptive afferents is specifically ablated by the injection of the neurotoxin saporin conjugated to the lectin IB4 (IB4-SAP) into the sciatic nerve. The animals did not display any pain-related behavioral changes. However, we observed a significant upregulation of NK-1r in lamina I, in neuronal types that normally expressed it (i.e. fusiform and multipolar cells), with no de novo expression by pyramidal neurons. In the third experimental chapter, we addressed the issue of whether lamina I projection neurons which express the NK-1r are innervated by non-peptidergic nociceptive afferents, as a study in a transgenic mouse model had provided data suggesting that non-peptidergic afferents had connections with deep dorsal horn neurons but not with lamina I NK-1r-expressing cells. We performed a systematic study aimed at identifying the normal connections of the non-peptidergic nociceptive fibers with lamina I neurons using both confocal and electron microscopy and we found a considerable innervation by non-peptidergic afferents on all three types of lamina I projection neurons. The results of this thesis, taken together with previous data from our lab, suggest that a chronic pain state, such as neuropathic pain, seems necessary to trigger a de novo expression of NK-1r in pyramidal neurons and their increased innervation by peptidergic afferents. Further studies are required to clarify the role, in normal nociception and chronic pain states, of the significant direct innervation of lamina I projection neurons by non-peptidergic afferents which we revealed for the first time.La douleur chronique est une condition débilitante ayant de sérieuses répercussions socio-économiques. L'objectif de cette thèse était de mieux comprendre l'organisation de la corne dorsale de la moelle épinière et les changements qui s'y produisent dans les cas de douleurs chronique neuropathique suite à une lésion du système nerveux. Nos études se sont concentrées sur deux composantes importantes des circuits de la douleur: les neurones de projection et leur innervation par les afférents nociceptifs de petit diamètre. Les neurones de projection de la couche 1 de la moelle épinière sont classées selon leur morphologie en 3 types: les neurones fusiformes, multipolaires et pyramidaux. Les deux premiers répondent aux stimuli douloureux et expriment le récepteur de la substance P (NK-1r), alors que les neurones pyramidaux n'expriment ce récepteur qu'occasionellent et répondent au froid non-douloureux. Les deux populations d'afférents principales sont les fibres de petit diamètre peptidergiques, qui expriment la substance P et le "calcitonin gene-related peptide" (CGRP), et les non-peptidergiques, qui sont dépourvues de neuropeptides et qui s'associent avec la lectine IB4. Lors du premier chapitre expérimental, nous avons étudié les changement qui se produisent dans la corne dorsale de la moelle épinière dans un modèle de douleur neuropathique chronique. Nous avons démontré une expression de novo du NK-1r sur les neurones pyramidales, un changement similaire à celui se produisant dans un modèle d'arthrite chronique. Ce changement de phénotype était associé à une augmentation significative du nombre d'appositions peptidergiques faites sur cette population neuronale, qui reçoit habituellement très peu de ces entrées. Afin de vérifier si ces récepteurs sont fonctionnels et répondent aux stimuli douloureux, nous avons injecté de la capsaicine dans la patte arrière, ce qui a mené à une internalisation du récepteur, marquant l'activation de celui-ci. Le deuxième chapitre de cette thèse vérifie si un état de douleur chronique est nécéssaire pour ce changement phénotypique, utilisant une lésion non douloureuse qui cause une augmentation signnificative du NK-1r dans la corne dorsale. Dans ce modèle, une population de nocicepteurs non peptidergiques est excise par une injection dans le nerf sciatique de la toxine saporine conjuguée à la lectine IB4 (IB4-SAP). En absence de symptômes douloureux, la couche 1 de la corne dorsale des animaux lésés a subi une augmentation générale du NK-1r mais sa distribution cellulaire est restée normale, sans expression de novo sur les cellules pyramidales.Lors du troisième chapitre de cette thèse, nous avons vérifié si les neurones de projection de la couche 1 exprimant le NK-1r recevaient des entrées des fibres nociceptives non peptidergiques, comme ce sujet était controversé suite à une publication utilisant des souris transgéniques démontrant une absence de connections de la sorte. Nous avons fait une étude systématique utilisant la microscopie confocale et électronique et avons démontré que les 3 types morphologiques de cellules de projection reçoivent des entrées non peptidergiques directes.Pris ensembles, les résultats de cette thèse suggèrent qu'une condition de douleur chronique est nécessaire pour l'expression du NK-1r sur les neurones pyramidaux et l'augmentation des entrées peptidergiques faites sur celles-ci. D'autres études seront nécessaires pour clarifier l'implication des entrées non peptidergiques faites sur les neurones de projection dans la nociception normale et dans la douleur chronique.
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Gkanatsiou, Eleni. "Mass Spectrometry Based Proteomics : Toward understanding neuropathic pain." Thesis, Uppsala universitet, Analytisk kemi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-297658.
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The aim of this project was to get insight into mass spectrometry based proteomics, get familiarized with novel techniques, and obtain the operating skills with modern Orbitrap mass spectrometers. In order to achieve this, the proteome changes in neuropathic pain responses corresponding to nerve injury side in individual rat’s spinal cord were explored. We focused in protein identification and quantification of the expressed proteins in 3 different set of samples, SNL, Sham and Naive rats.
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Rockett, Mark Peter. "The contribution of AMPA receptors to neuropathic pain." Thesis, University of Edinburgh, 2005. http://hdl.handle.net/1842/29971.
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This study was designed to investigate the role of AMPA, NMDA, mGlu group I and VPAC2 receptors (Rs) in the generation of neuropathic pain. Firstly, the behavioural reflex responses of naïve rats to intrathecal administration of low doses of these receptor agonists, singly or in combinations were investigated. Combinations of two or more agonists caused increased behavioural responses to thermal and mechanical stimuli. The combination of AMPA with mGluR group I and VPAC2R agonists, showed a synergistic effect whereas other combinations were less then additive. Expression of AMPA receptor GluR1 and GluR2 subunits in the superficial dorsal horn was studied using confocal immunofluorescence. In the chronic constriction injury (CCI) model of neuropathic pain both the number of GluR1-immunpositive cell bodies and the level of GluR1 expression in cells decreased significantly in lamina II of the dorsal horn, ipsilateral to the injury. In contrast, there was no change in GluR2 expression or the degree of colocalisation of GluR1 and GluR2 receptor subtypes within individual cells following CCI. The subcellular distribution of GluR1 subunits was also noted to change significantly as a result of CCI. GluR1 subunits were found to redistribute distally into neuronal processes in lamina II cells ipsilateral to CCI and also in response to acute intrathecal AMPA treatment. This redistribution may reflect an increase in the number of GluR1-containing receptors associated with synaptic sites. The relationship between the presynpatic marker protein, bassoon and GluR1-immunopositive cells was investigated showing a significant increase in the number of bassoon immunopositive puncta associated with each GluR1-immunopositive cell ipsilateral to nerve injury. These results suggest that AMPA receptors are important in the central sensitisation underlying neuropathic pain. However, it is clear that several receptors are involved in triggering maximal behavioural responses, and potential therapeutic interventions may be more effective if designed to target more than one receptor type. There is also evidence to suggest that AMPA receptors may have differing roles dependent upon their subtype composition, so subtype-specific antagonists may potentially be useful in treatment of neuropathic pain.
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O'Neill, Francis. "Mechanistic comparison between spinal and trigeminal neuropathic pain." Thesis, University of Edinburgh, 2005. http://hdl.handle.net/1842/29928.
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For this study, we used rodent models of chronic constriction injury of sciatic or trigeminal nerve to investigate the electrophysical responsiveness of single neurones to mechanical stimuli. This strategy allowed comparison of the degree of sensitisation in the two areas. We also examined changes in expression of NMDA receptor subunits and MAGUK proteins. Our results show a marked facilitation of responsiveness in thermal and mechanical behavioural reflexes in both spinal and trigeminal neuropathic pain models. Electrophysiological experiments indicated an increase in responsiveness of individual neurons to mechanical stimulation in spinal neuropathic animals but this increase was not as pronounced in trigeminal neuropathic animals. Further differences in electrophysiological response characteristics to various peripheral sensory stimuli between spinal and trigeminal neurons were shown in normal animals and following nerve injury. Biochemical experiments revealed that changes in expression of some NMDA receptor subunits, as well as associated MAGUK proteins, differed between spinal and trigeminal neuropathic animals, and within different regions of the trigeminal complex itself. We further investigated the potential role of proteins such as Persyn (known to influence cytoskeletal network integrity) and α-synuclein (implicated in cell death), which may particularly influence the development, duration or recovery from neuropathic pain. We investigated the role of persyn and α-synuclein proteins in neuropathic pain, using two null-expression mutant mouse strains. However, no significant differences were observed between phenotypes of these mutant animals and wild type animals following nerve injury. In conclusion, this study provides evidence for mechanistic differences in neuropathic sensitisation between trigeminal and spinal regions. These differences may lead to targets for improved therapeutic treatment of intractable pain states.
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Hall, Sara M. "Bradykinin Ligands and Receptors Involved in Neuropathic Pain." Diss., The University of Arizona, 2015. http://hdl.handle.net/10150/578606.
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Neuropathic pain is a prevalent disease with no effective, safe treatments and limited knowledge on the mechanisms involved. One target for neuropathic pain treatment may be the blockade of Dynorphin A (Dyn A). Dyn A is a unique endogenous ligand that possesses well-known neuroinhibitory effects via opioid receptors and neuroexcitatory effects that are mediated through the bradykinin 2 receptors (B2Rs). Extensive SAR was carried out to develop a ligand for the blockade of the excitatory actions of Dyn A at the B2R. A lead ligand was able to block Dyn A-induced hyperalgesia in naïve animals and was effective in a neuropathic pain model. However, the ligand was susceptible to enzymatic degradation. In an effort to increase the stability, modifications of the ligand using non-natural amino acids were performed. Analogues substituted at or near the N-terminus with a D-isomer retained binding at the receptor as well as provided a large increase in stability. These ligands were also found to be non-toxic in a cell toxicity assay. Dyn A has been found to not activate the classical signaling of the B2R, PI hydrolysis or Ca²⁺ mobilization. In an effort to determine Dyn A's signaling, a study was done examining up-regulation of phosphorylated proteins. It was found that Dyn A did not activate; pERK, 7 PKC isoforms or PKA. A well known B2R antagonist, HOE140, was found to have low affinity at rat and guinea pig brain B2Rs but high affinity in the guinea pig ileum. Further examination revealed that this discrepancy in binding may arise from a different isoform of the B2R that has not been previously examined. To date, we have discovered Dyn A analogues that have high affinity for the B2R, are very stable, and have low toxicity. The signaling pathway is still not fully understood, but further studies are underway. Also, there is evidence that the B2R in which the analogues are interacting at may be a different form than what has previously been described. Targeting this different isoform of the B2R with our current stable ligands may provide beneficial therapeutics for the treatment of neuropathic pain without the cardiovascular liabilities.
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CAZZATO, Daniele. "Clinical and genetic characterization of neuropathic pain through the model of small fiber neuropathy: implication for diabetic neuropathy." Doctoral thesis, Università degli studi di Ferrara, 2020. http://hdl.handle.net/11392/2478814.
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Il dolore neuropatico è una caratteristica frequente delle neuropatie periferiche, in particolare quando sono coinvolte le piccole fibre nervose che veicolano la sensibilità termo-dolorifica. La neuropatia delle piccole fibre (SFN) tipicamente si presenta con dolore urente distale agli arti e rappresenta un buon modello per lo studio del dolore neuropatico. Mutazioni nei geni dei canali del sodio voltaggio dipendenti (VGSC) sono state descritte in sindromi algiche familiari e nell’insensibilità congenita al dolore. Più recentemente, varianti in questi geni sono state identificate in associazione a condizioni più comuni quali le neuropatie dolorose. Obiettivo di questa tesi è di indagare il rischio di dolore neuropatico in una coorte ben caratterizzata di pazienti affetti da SFN e neuropatia diabetica. Nella prima sezione sono stati indagati gli aspetti clinici mediante una dettagliata caratterizzazione fenotipica dei pazienti con sospetto di SFN e dolore neuropatico, attraverso la progettazione di un database per la raccolta sistematica dei dati, l'integrazione e la condivisione tra medici e ricercatori. Tali dati sono stati utilizzati per condurre due studi retrospettivi. Il primo ha valutato l'accuratezza diagnostica della biopsia cutanea nel tempo, confrontando i diversi valori normativi per la densità di innervazione intraepidermica adottati dal 1999 al 2019. I risultati su 439 pazienti hanno evidenziato un significativo miglioramento della specificità diagnostica della biopsia cutanea dopo l'introduzione dei valori normativi corretti per età e sesso nel 2010, con una riduzione dei falsi positivi di oltre il 50%. Il secondo studio ha indagato le variazioni circadiane dell'intensità del dolore neuropatico in una coorte di 253 pazienti con sospetta SFN dolorosa rivelando un significativo incremento dell’intensità del dolore dal mattino/pomeriggio alla sera. Lo studio ha mostrato un pattern circadiano del dolore neuropatico che potrebbe fornire una misura di outcome aggiuntiva negli studi clinici per il trattamento del dolore neuropatico nella SFN. La seconda sezione include due studi finalizzati ad identificare determinanti genetiche associate a diversi fenotipi clinici in relazione all’eziologia e alla presenza o assenza di dolore neuropatico. Una prima analisi è stata effettuata su geni candidati, ricercando varianti rare e a bassa frequenza nei geni VGSC potenzialmente esercitanti maggiore effetto sul fenotipo clinico. L'analisi condotta su 1.015 pazienti ha mostrato una maggiore frequenza di varianti rare nei geni VGSC in pazienti con dolore rispetto al fenotipo senza dolore (13,5% e 9,7%) ma nessuna differenza significativa dividendo il campione sulla base dell’eziologia diabetica o idiopatica (11,5%). Osservando la distribuzione delle varianti nei geni VGSCs, i pazienti idiopatici e quelli con dolore presentavano una frequenza significativamente più alta di varianti in SCN9A, mentre nei pazienti con diabete e in quelli senza dolore prevalevano varianti nel gene SCN10A. Tuttavia, la maggior parte di queste varianti sono state classificate come VUS (varianti di significato sconosciuto), pertanto esistono dubbi circa il loro reale significato patogenetico. Sulla base dell'ipotesi di un'architettura poligenica della neuropatia dolorosa in cui tutte le varianti, sia rare che comuni, possono contribuire al fenotipo clinico, è stato adottato un nuovo approccio per indagare il rischio di dolore neuropatico nei pazienti con diabete. E’ stato calcolato un punteggio di rischio poligenico (PRS) combinando il peso di ogni variante identificata in un pannello di 107 geni correlati al dolore, in pazienti affetti da neuropatia diabetica con e senza dolore. Il PRS è stato in grado di discriminare con una sufficiente accuratezza pazienti con dolore da quelli senza dolore. Questo studio rappresenta la prima applicazione del PRS nello studio del dolore neuropatico associato a neuropatia diabetica.Neuropathic pain is a frequent feature in peripheral neuropathy in particular when small nerve fibers, which convey thermal and nociceptive sensations, are involved. Excruciating burning pain at feet and hand is the most common feature of small fiber neuropathy (SFN) which represents a good model for studying neuropathic pain. Voltage gated sodium channel (VGSCs) genes mutations have been found in rare familial painful disorders and more recently, variants in the same genes have been identified in idiopathic and diabetic painful neuropathies, thus widening the spectrum of genetic pain disorders. This PhD thesis aimed at investigating the risk for neuropathic pain in a well-phenotyped cohort of SFN and diabetic neuropathy patients in order to provide a clinical and genetic characterization of patients. The first section focused on the deep-phenotyping of patients with suspected SFN or neuropathic pain through the development of a database for systematic data collection, integration and sharing among clinicians and researchers. Collected data have been used to conduct two retrospective studies. The first study aimed at addressing the diagnostic accuracy of skin biopsy over time comparing the different normative values for intraepidermal nerve fiber density (IENFD) adopted from 1999 to 2019. This study, comparing skin biopsy results in 439 patients according to different cut-off values, showed a significant improvement of skin biopsy diagnostic specificity after the introduction of the age-and-sex-adjusted normative reference values in the 2010, reporting a reduction of false positive of more than 50% when compared with the cut-off values previously adopted. The second study investigated the circadian dynamics of neuropathic pain intensity scored using the numeric rating scale (PI-NRS) in a cohort of 253 patients with suspected painful SFN. This study revealed a circadian pattern of pain features, showing an increase of NRS scores towards the evening, suggesting a possible role for the intra-day PI-NRS variations as adjunctive outcome measure in clinical trials for analgesic drug in SFN-related neuropathic pain. The second section of the thesis provided a genetic characterization of SFN patients. A candidate-gene analysis has been conducted, looking for rare and low frequency genetic variants in VGSCs genes expected to have a large effect on clinical phenotype and describing their frequency in phenotypically well-defined cohorts of SFN patients. The analysis conducted on 1,015 patients grouped according to etiology and painful phenotype showed a slightly higher frequency of VGSCs variants in painful compared to painless phenotype (13.5% and 9.7%, respectively) but no significant differences between diabetes and idiopathic SFN patients (11.5%). Looking at the variants distribution in VGSCs genes, idiopathic and painful patients showed a significant higher frequency of SCN9A variants whereas diabetes and painless patients had more variants in SCN10A gene. However, concerns have been raised about the pathogenicity of single rare gain-of-function variants, since most of them were classified as VUS (variants of unknown significance). Based on these findings, we adopted a new research approach to investigate the risk of neuropathic pain in our diabetic cohort of 513 patients. The work hypothesis relied on a polygenic architecture of painful neuropathy in which all variants, whether rare or common, might contribute with a small effect size to compose the clinical phenotype. Therefore, we computed a polygenic risk score (PRS) combining the weight of each variant identified in a panel of 107 pain-related genes in diabetic neuropathy patients. The PRS was able to discriminate with sufficient accuracy painful from painless patients with an AUC of 60.3%. This study represented the first application of PRS for addressing the risk of neuropathic pain in diabetic neuropathy, pioneering the use of this tool in this clinical context.
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Caspani, Ombretta [Verfasser]. "Cold transduction mechanisms during peripheral neuropathic pain / Ombretta Caspani." Berlin : Freie Universität Berlin, 2008. http://d-nb.info/1023169932/34.
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Rose, Kirstin Elizabeth. "The role of the M channel in neuropathic pain." Thesis, University of Leeds, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.521479.
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Chew, Daniel John. "Mechanisms involved in chronic neuropathic pain after avulsion injury." Thesis, Queen Mary, University of London, 2010. http://qmro.qmul.ac.uk/xmlui/handle/123456789/445.
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Motor vehicle accidents are the most common cause of injuries involving avulsion of spinal roots from the brachial or lumbosacral plexuses. This results in chronic intractable pain that is refractory to pharmacotherapy. This is largely due to lack of information on underlying mechanisms, and lack of an established animal model to test drug treatments. This thesis has: 1) compared the neuroanatomical effects of dorsal root rhizotomy (DRR) and avulsion (DRA) in the spinal cord. DRR is commonly used to model avulsion injury but unlike avulsion it does not damage the spinal cord, as often happens clinically. 2) Developed a behavioural model of spinal root avulsion injury (SRA). 3) Evaluated the behavioural effects of drugs prescribed to treat neuropathic pain or those used clinically to treat other conditions like motoneuron disease or spinal cord injury. DRA produced a greater and prolonged glial, inflammatory, vascular response and cell loss than DRR. SRA produced thermal and mechanical hypersensitivity in the affected hind-paw. Neurodegenerative and neuroinflammatory responses were observed in both the avulsed and adjacent spinal segments, but produced no changes in the neuronal phenotype adjacent dorsal root ganglion neurons, suggesting that the evoked behaviour is mediated by central mechanisms. Administration of amitriptyline or carbamazepine reduced behavioural hypersensitivity in SRA, confirming their limited clinical efficacy in treatment of avulsion injury. Minocycline and riluzole produced therapeutic efficacy. Both compounds prevented the establishment of behavioural hypersensitivity, which correlated histologically with microglial inhibition, although riluzole was transiently effective. Additionally, minocycline reversed the hypersensitivity, an effect that persisted beyond drug washout, whereas riluzole had a limited effect that only lasted whilst the drug was administered. This thesis provides insight into the mechanisms of avulsion-induced neuropathic pain. The establishment of a behaviourally reproducible avulsion model provides a platform to test new pharmacological candidates for treatment, such as minocycline.
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Buckley, David A. "Improving the diagnosis and treatment of chronic neuropathic pain." Thesis, University of Huddersfield, 2018. http://eprints.hud.ac.uk/id/eprint/34551/.
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Chronic neuropathic pain (CNP) occurs as a consequence of injury to the nervous system. Despite recent advances, CNP lacks objective diagnostic criteria, is often unrelenting and refractory to treatment. The primary aims of this thesis are twofold; the identification of CNP biomarkers using both human cohorts and an animal model (spinal nerve ligation; SNL) of neuropathic pain, and to provide clarity on the role of GTP cylcohydrolase I (GCH1) in CNP. Analysis of GCH1 and related genes and metabolites was conducted. As biomarkers, nitrite/nitrate and neopterin did not differentiate controls from CNP patients. However, significant differences were observed with biopterins, whilst correlations were observed between GCH1, nitrite/nitrate and neopterin, which were notably stronger in patients than controls. Analysis in human cohorts and in the SNL model also inferred that downregulation of GCHFR may contribute to BH4 synthesis. In order to provide clarity on the role of the GCH1 pain protective haplotype, reporter gene assays were used. This demonstrated a potential regulatory role for the GCH1 5’ SNP (rs8007267). In silico prediction of transcription factor binding sites suggested that this may be mediated by the aryl hydrocarbon nuclear translocator. The use of electrophoretic mobility shift assays showed strong specific binding with probe pertaining to the major allele. Further analysis is required to elucidate transcription factor binding, potentially facilitated by 2D-PAGE and mass spectrometry. In order to further elucidate potential CNP biomarkers, microarray analysis and qRT-PCR were performed using blood obtained from CNP patients. Data refinement led to the isolation of 27 potential CNP biomarkers, of which several cross-validated between cohorts. Microarray data, literature evidence, and correlations with previous microarrays provided evidence suggestive of a role for TIMP1. Multiple other genes, including CASP5, TLR4, TLR5, MC1R and CX3CR1, were differentially regulated in CNP. Genes surviving microarray data refinement were subsequently analysed in the dorsal horn of Sprague Dawley and Wistar Kyoto rats after SNL. Several genes, including Dpp3, Mc1r and Timp1, were similarly differentially expressed in the rodent SNL model, which suggests that these genes may be involved in the pathophysiological mechanisms of CNP, and may also function as potential translational biomarkers of CNP. This work provides multiple avenues for expansion and further investigation. Clearly, the challenges associated with biomarker discovery in CNP states are considerable, though it is hoped that this thesis provides valuable insight and the necessary foundation for future work.
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Emraja, Ahmed M. M. "Animal models of neuropathic pain after spinal cord injury." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4176/.
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Approximately 70% of spinal cord injured patients suffer from pain and it is estimated that in 40-50% of these, the pain is of central neuropathic origin. This pain can be perceived to originate at, or below the level of injury and both evoked and spontaneous pain can occur. Neuropathic pain after spinal cord injury (SCI) is difficult to treat and often poorly controlled by the currently available analgesics so that development of better treatments is an important need. Current ideas about the treatment of SCI pain are that different approaches may be needed to treat the different types of pain (e.g. evoked and spontaneous, at level and below level) as they may have different mechanisms. However, this mechanistic approach to treatment is hampered by a poor understanding of the underlying mechanisms. This in turn depends on development of animal models and pain assessment techniques suitable for mechanistic studies. In this thesis, several rodent SCI models have been investigated using a range of assessment techniques some of which were developed in the course of the study. Contusion injuries at a low thoracic level are currently the most popular model used to investigate central neuropathic pain in rodents. However this model and the assessments used with it are subject to a number of limitations. We therefore began by re-evaluating this model using a relatively severe (200 kdyn) injury since this is indicated in the literature as being necessary for the development of robust signs of neuropathic pain. We found that this model showed robust signs of tactile allodynia and thermal hyperalgesia of the forepaws and in addition by developing new tests, were able to demonstrate cold allodynia and hyperalgesia. Although the hindpaws also showed responses that would normally be interpreted as mechanical allodynia and thermal hyperalgesia, the absence of accompanying supraspinally mediated behaviours (including licking following heat stimuli) indicated that the enhanced responsiveness to these stimuli might not give rise to pain. Further investigation using operant testing supported this idea and tract tracing suggested that this may be due to substantial interruption of ascending nociceptive pathways. Testing over the back at locations confirmed electrophysiologically to involve sensory processing at, above and below the injury level supported the idea that increased sensitivity in this model developed at and above, but not below level. In addition, observations on the forepaws suggested evidence of spontaneous pain which has never been described in SCI models previously and provides an important opportunity for studying the underlying mechanisms. Because the 200 kdyn low thoracic model proved unsuitable for the study of below level pain we next investigated whether a less severe injury at this level would provide a better model. Injuries of 150 kdyn were found to result in most of the same indicators of pain following forelimb testing as were seen following 200 kdyn injuries but all signs were less pronounced, in particular, indicators of evoked pain. Testing over the back led to increased sensitivity below level which had not been evident in the 200 kdyn model, providing an opportunity for below level testing. However, interpretation of hindpaw tests remained equivocal. Because the low thoracic model showed features that suggested forelimb assessments were particularly useful for the assessment of above level pain of different modalities as well as spontaneous pain, we investigated the effect of moving the injury closer to the segments assessed by such tests. Injuries at the T3/T4 level were found to lead to enhancement of all of the behavioural signs seen in the 200 kdyn low thoracic injury animals, especially signs of spontaneous pain. This model may therefore be optimum for the assessment of above/at level pain. The work presented in this thesis provides the clearest and most comprehensive data yet on the utility of models of SCI for the investigation of central neuropathic pain and represents a significant advance in the field. The finding that injuries at low thoracic levels may (depending on injury severity) be unsuitable for assessment of below level pain has implications for previous studies of the mechanisms of post SCI pain, many of which have used exclusively hindlimb assessments in these models. The hope is that an improved understanding of the models used here and an improved ability to investigate different modalities of evoked pain, and in addition spontaneous pain, will enhance the quality of future research in this area and lead to both a better understanding of central neuropathic pain mechanisms and the development of more effective analgesics for this type of pain.
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Hechler, Ashley C. "Identifying and Treating Neuropathic Pain in Dogs with Syringomyelia." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1554712901697936.
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Legg, Ewen. "Behavioural co-morbidities in rat models of neuropathic pain." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/9070.
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Pain is a complex experience involving both sensory and emotional aspects. Neuropathic pain syndromes, which remain a major area of unmet clinical need, are often associated with behavioural co-morbidities such as anxiety and depression. Recent studies have demonstrated changes in a number of affect-related outcome measures in rodent models of neuropathic pain. The expansion of such outcome measures offers one possible route for the improvement of studies aimed at creating novel therapies for neuropathic pain. Bias reduction through randomisation requires mixed housing of animals with peripheral nerve injuries with non-injured conspecifics. Such mixed housing was shown to alter behaviour in the open field. Therefore, in the following studies treatments were allocated to cage groups as a whole. Anxiety-like behaviour was demonstrated in L5 spinal nerve transected (L5 SNT) rats in a novel dark/light preference test and the utility of this test in detecting efficacious analgesics was investigated. The possible presence of neuropathy-induced depression-like behaviour following L5 SNT was then investigated using the forced swim test. However, animals showed no increase in depression-like behaviour, as measured by time spent immobile in the forced swim test, at either two or three weeks post-neuropathy. Assessment of burrowing behaviour, a novel behavioural outcome measure thought to reflect over all well being in rodents, was then carried out in rats following L5 SNT and partial sciatic nerve ligation. A reduction in burrowing behaviour was demonstrated in both models of neuropathic pain compared to naive animals. The use of novel outcome measures, such as those detailed above, both as outcome measures in drug development and in studies into pathophysiology will improve the quality of studies aimed at creating novel therapies for neuropathic pain.
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McCormick, Barry. "Antioxidant protection in mitochondria in chemotherapy-induced neuropathic pain." Thesis, University of Aberdeen, 2015. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=229728.
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Neuropathic pain is a common and dose-limiting adverse effect of several cancer chemotherapeutic agents including paclitaxel. Current treatments for chemotherapy-induced peripheral neuropathy (CIPN) are largely ineffective and the pain can persist long after the cessation of the chemotherapy regimen. Whilst the specific underlying mechanisms are not fully understood, oxidative stress and mitochondrial damage are thought to be involved in the development of CIPN. Antioxidants which protect mitochondria may inhibit oxidative stress and protect mitochondrial function more effectively than antioxidants which do not specifically act within mitochondria, and may attenuate CIPN. The overall aim of the study was therefore to determine the effects of mitochondrial-targeted antioxidants on CIPN. This was addressed in two main parts. Firstly, in vitro studies aimed to determine the effects of paclitaxel alone and in combination with mitochondrial-targeted antioxidants melatonin and MitoVitE, and a non-targeted antioxidant, Trolox, on oxidative stress and mitochondrial function in cells. In vivo studies aimed to determine the effects of melatonin, MitoVitE and Trolox in a preclinical rat model of paclitaxel neuropathic pain. In vitro studies used a dorsal root ganglion (DRG) cell line (50B11). Cells were cultured with a range of concentrations of paclitaxel, with or without the addition of melatonin, MitoVitE or Trolox. Several measures of oxidative stress including free radical production, and glutathione levels, and measures of mitochondrial function, including mitochondrial metabolic rate, membrane potential, mitochondrial pore opening and ATP production were made. In vivo studies used a rat model of paclitaxel-CIPN, and assessed the effects of melatonin, MitoVitE and Trolox on behavioural measures of pain. In vitro studies showed that paclitaxel induced oxidative stress and caused mitochondrial damage in the DRG cell line. Compared to paclitaxel alone, cells co-treated with melatonin and MitoVitE had reduced oxidative stress and mitochondrial damage. Co-treatment of cells with paclitaxel and Trolox did not differ from conditions with paclitaxel only. In vivo studies demonstrated that melatonin and MitoVitE attenuated paclitaxel-induced mechanical hypersensitivity, whilst Trolox did not affect behavioural measures of CIPN. These studies suggest that mitochondrial-targeted antioxidants may be useful as a potential treatment strategy for CIPN.
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PICCI, CRISTINA. "Exploitation of new pharmacological targets for neuropathic pain reliefe." Doctoral thesis, Università degli Studi di Cagliari, 2015. http://hdl.handle.net/11584/266610.
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Neuropathic pain is a complex chronic condition which affects the somatosensory system, poorly managed with the conventional treatments despite the immense advances in pain treatment strategies. Damage of peripheral nervous system, due to injury or disease, leads to abnormal responses to painful and not-painful stimuli; conventional analgesics can only alleviate pain in acute situation, and finding an effective treatment which can relief chronic neuropathic pain remains still challenging.
Mammalian STOML3, a MEC-2 homologue, is a member of a large family of stomatin proteins characterized by a common stomatin domain, expressed by DRG sensory neurons involved in regulation of mechanosensation, which is required for normal mechanoreceptor function. Previous data revealed that in STOML3 null mice 30-40% of Aδ and Aβ fibers lacked all mechanosensitivity; in addition, tactile behaviors are impaired and symptoms of neuropathic pain in CCI mice are also largely attenuated (Wetzel et al, 2007).
Here I investigated the mechanisms by which STOML3 acts as an important contributor in the neuropathic pain symptoms and I demonstrate that small molecule modulation that both reversibly silence mechanoreceptors in vivo and attenuate touch perception in mice can reverse established neuropathic pain symptoms, making STOML3 a promising novel peripheral target for the treatment of sensory disorders.
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Trovato, A. E. "Endocannabinoid and purinergic systems in rodent neuropathic pain model." Doctoral thesis, Università degli Studi di Milano, 2008. http://hdl.handle.net/2434/63077.
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Schweinhardt, Petra. "Neural correlates of clinical pain processing in neuropathic and inflammatory pain patients and comparison with experimental pain." Thesis, University of Oxford, 2006. http://ora.ox.ac.uk/objects/uuid:12e71d31-24f8-47e8-ba83-129575007644.
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The goal of this thesis was to examine the processing of clinical pain in two patient groups with well defined primary pathologies, i.e. neuropathic pain patients and patients with rheumatoid arthritis (RA). It was hypothesized that chronic pain is associated with plastic changes in pain processing brain structures that can be detected using functional magnetic resonance imaging (FMRI). The first study, presented in Chapter 3, demonstrates that the neural representation of experimental heat pain is different in neuropathic pain patients than in age- and gender-matched healthy control subjects, although the pain stimulus was applied outside clinically affected areas. Increased activation was found in amygdala and anterior insula in the patient group and was accompanied by increased state anxiety and depression scores. Anterior insula is the focus of Chapter 4 in which it is demonstrated that clinical pain processing is located significantly more anteriorly in the insula than experimental pain processing, in close proximity to neural correlates of highly negative emotions and the conscious perception of bodily sensations. This offers a potential explanation for the shift of clinical pain processing. In Chapter 5, clinical pain is contrasted with experimental pain in the same patient population, i.e. patients with RA. In addition to comparing clinical and experimental pain processing, it was investigated if emotional and cognitive determinates of the pain experience, specifically depression and catastrophizing, exert different influences on the two types of pain. It is shown that clinical pain, but not experimental pain, is likely to be driven partially by depressive symptoms whereas catastrophizing is associated with the same neural activation pattern in both conditions. The cerebral representation of allodynic pain in neuropathic pain patients is presented Chapter 6. Chapters 6 and 7 demonstrate that the FMRI signal encodes the perceived intensity of clinical allodynic pain across subjects and that it reflects longitudinal variations of the perceived intensity within subjects. This thesis illustrates that FMRI can reveal subtle differences in the processing of clinical and experimental pain, despite brain activation patterns being similar on the whole. It also indicates that FMRI can be used to elucidate the origin of these differences, for instance by studying the influence of emotional and cognitive variables. This suggests that neuroimaging methods, in particular FMRI, have the potential to dissect clinical pain into its constituent parts, including central sensitization, brainstem facilitation and amplification by psychological factors. Such knowledge could potentially be exploited to target treatment selectively at different components of clinical pain and to monitor longitudinal changes of these components separately.
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Yilmaz, Zehra Tijen. "Expression and activity of pain receptors in health and neuropathic pain of the mouth." Thesis, Queen Mary, University of London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498599.
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Abdul, Aziz Che Badariah. "Thalamic nociceptiive processing in rat models of acute inflammatory pain and chronic neuropathic pain." Thesis, University of Nottingham, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.410465.
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Myers, Alyssa Michelle. "Single and Combined Effects of Cannabinoids on Neuropathic Pain and Cognition." Master's thesis, Temple University Libraries, 2016. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/378041.
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Biomedical SciencesM.S.
Rationale. For centuries, medications derived from the marijuana plant have been used for therapeutic purposes across numerous cultures. In 1964, the primary psychoactive ingredient in cannabis, delta-9-tetrahydrocannabinol (-9-THC) was defined. This, followed by the discovery of the endocannabinoid system, marked the beginning of comprehensive research into the beneficial exploitation of this system. The cannabis plant contains various other cannabinoids besides -9-THC. Most of the effects of cannabinoid-based therapies are based on the agonistic action of -9-THC through cannabinoid receptors. Alternatively, some of these effects are caused by the actions of other cannabinoids, like cannabidiol, which does not have high affinity for cannabinoid receptors. Like -9-THC, cannabidiol (CBD), the non-psychoactive phytocannabinoid in Cannabis sativa, has been hypothesized to ameliorate adverse effects of -9-THC. Cannabidiol possesses neuroprotective, antiemetic, and anti-inflammatory properties. Sativex, a 1:1 ratio of CBD and -9-THC, is currently an approved medication in Europe for the treatment of conditions such as neuropathic pain, and has been fast tracked by the USFDA for late stage clinical trials for a host of disorders, ranging from epilepsy to irritable bowel disease. Additionally, increasing preclinical evidence demonstrates that treatment with Cannabidiol alone produces efficacy on a variety of nervous system injuries, including neuropathic pain, schizophrenia and anxiety disorders. Furthermore, there is mounting evidence of an “entourage effect” in cannabinoid-based pharmacotherapies. This effect occurs when treatment with a combination of cannabinoids derived from the plant produce more efficacy than treatment with a single cannabinoid (1). As cannabinoid-based treatments continue to develop and clinical data increases, further investigation of the entourage effect is necessary to facilitate the appropriate future treatment regimens for nervous system disorders. Hypotheses. We hypothesized that treatment with the non-psychoactive cannabis compound cannabidiol would be as effective as the psychoactive cannabis compound -9-THC, or a combination of the two, in mitigating neuropathic pain in a mouse model of chemotherapy-induced peripheral neuropathy. We additionally hypothesized that cannabidiol would not affect classic cannabinoid-agonist induced cognitive impairment in rodent models of learning and memory. Methodology. Neuropathic pain was induced by repeated injections of the chemotherapeutic agent Paclitaxel. Mechanical hypersensitivity to Paclitaxel was assessed using the Von Frey assay. Cognition was assessed using three rodent models of learning and memory: 1) Conditional Discrimination, 2) Conditional Discrimination with a reversal component, and 3) Barnes Maze. Results. Cannabidiol was found to be more potent and more effective than -9-THC in attenuating neuropathic pain in a dose dependent manner. Combinations of CBD+-9-THC revealed that lower, ineffective doses of CBD and -9-THC display supra-additive effects when given in combination while higher, individually effective doses exhibit sub-additive effects in combination. Cognitively, no deficits were observed over a range of doses of any cannabinoid tested in the conditional discrimination tasks, although a slight trend was observed in animals administered the synthetic mixed CB1/CB2 agonist WIN55,212-2. In the Barnes Maze task, treatment with -9-THC alone dose-dependently decreased number of entries and total time spent in the target zone. Cannabidiol did not produce any effects in the Barnes Maze alone, nor did it attenuate the effects seen in animals treated with -9-THC alone. Lastly, -9-THC did not affect total distance traveled or average speed, whereas combination treatment increased both locomotor measurements at all but the highest combination dose. Conclusions. The results of these studies indicate that cannabidiol is more potent than -9-THC in attenuating neuropathic pain. Results of cognitive testing indicate subtle impairment in animals treated with -9-THC and WIN55,212-2 that were not reversed by CBD.
Temple University--Theses
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Fiore, Nathan Troy. "Neuroimmune interactions related to development of affective behavioural disturbances in neuropathic pain states." Thesis, The University of Sydney, 2019. http://hdl.handle.net/2123/20984.
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Nerve damage leads to the development of disabling neuropathic pain in susceptible individuals, where patients present with pain as well as co-morbid behavioural changes, such as anhedonia, decreased motivation and depression. The pathophysiology of neuropathic pain remains unknown, however accumulating evidence suggests that neuroimmune interactions play a key role in its pathogenesis and development of co-morbid behavioural disturbances. Complex regional pain syndrome (CRPS) is a debilitating neuropathic disorder where trauma to a limb results in chronic pain. Mass cytometry (CyTOF) was used to systematically analyse circulating immune cells with a panel of 38 phenotypic and activation markers in the blood of CRPS patients and healthy controls. CyTOF revealed an expansion and increased activation of signalling pathways in several distinct populations of central memory CD8+ and CD4+ T lymphocytes. Regarding emotional state, CD8+ T lymphocytes were correlated with clinical scores for stress and CD4+ Th1 lymphocytes correlated with clinical scores for anxiety. There was also a reduction in circulating Dendritic cells (DC), indicative of DC tissue trafficking and potential involvement in lymphocyte activation. These data highlight a pathogenic role for T lymphocyte mediated chronic inflammation in CRPS and co-morbid behavioural disabilities. To further explore to role of neuroimmune interactions in the development of neuropathic pain and co-morbid behavioural changes, a rodent nerve injury model was utilized to evaluate whether individual differences in radial maze behaviour and neuroimmune interactions in the hippocampus (HP) and medial prefrontal cortex (mPFC) occurred in rats after sciatic nerve chronic constriction injury (CCI). CCI reduced mechanical withdrawal thresholds in all rats, whilst pellet-seeking behaviours were altered in some but not all rats. One group, termed ‘No effect’, had no behavioural changes compared to sham rats. Another group, termed ‘Acute effect’, had a temporary alteration to their exploration pattern, displaying more risk-assessment behaviour in the early phase post-injury. In a third group, termed ‘Lasting effect’, exploratory behaviours were remarkably different for the entire post-injury period, showing a withdrawal from pellet-seeking. Immunohistochemical analysis throughout the dorso-ventral axis of the HP revealed that the withdrawal from pellet-seeking observed in Lasting effect rats was concomitant with distinct glial-cytokine-neuronal adaptations within the contralateral ventral HP, including; increased expression of IL-1b and MCP-1; astrocyte atrophy and decreased area in the dentate gyrus (DG); reactive microglia and increased FosB/DFosB expression in the cornu ammonis (CA) subfield. These data highlight that glial-cytokine-neuronal adaptations in the ventral HP may mediate individual differences in radial maze behaviour following CCI. A follow up experiment explored whether pre-injury learning on the maze altered the effects of nerve injury on exploratory behaviour and spatial memory function. Whilst CCI again produced three distinct patterns of behaviour on the radial maze, Acute effect rats had improved working spatial memory outcomes after CCI. This indicates that the increased risk-assessment behaviours employed by Acute effect rats after injury may be considered advantageous when pellet-seeking, as it reduces unnecessary exploration during reward-seeking. The behavioural disruptions observed in Lasting effect rats were accompanied by neuroimmune activation within the contralateral ventral HP and mPFC. Multiplex immunoassay analysis revealed an increase in IL-1b, IL-6 and MCP-1 within the contralateral mPFC and ventral HP. Detailed immunohistochemical analysis of the mPFC and HP revealed an increased expression of IL-6, increased phospho-p38 MAPK expression in neurons and microglia, and a shift to a reactive microglial morphology in the caudal prelimbic and infralimbic cortex, ventral CA1 and DG. There was also a reduction in astrocyte cell size and BDNF expression in the contralateral ventral DG. These data provide further evidence that neuroinflammation in the mPFC and ventral HP may influence individual differences in radial maze behaviour following CCI. Collectively, these data provide evidence that individual differences in circulating immune cell activation and neuroimmune signature in the interconnected ventral HP-mPFC circuitry may play a significant role in the divergent behavioural trajectories in the neuropathic pain state, contributing to co-morbid behavioural changes in susceptible individuals.
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Kvarnström, Ann. "Neuropathic Pain; Quality of Life, Sensory Assessments and Pharmacological Treatments." Doctoral thesis, Uppsala University, Department of Surgical Sciences, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3766.
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Neuropathic pain of central and peripheral origin presents a substantial clinical problem as it is often resistant to pharmacological treatment.
The health related quality of life of 126 patients with peripheral neuropathic pain was studied, to provide a cross sectional description from this point of view. Two generic health-related quality of life instruments; the SF-36 and the Nottingham Health Profile were used together with pain assessments, global rating of health and verbal rating scales of pain and other symptoms, as well as patient descriptors.
The analgesic effect of ketamine, lidocaine and morphine were assessed in a double blind, placebo-controlled, randomized study design. Three groups of patients were studied: patients with peripheral neuropathic pain of traumatic origin, patients with central post-stroke pain and patients with neuropathic pain after spinal cord injury. Somatosensory function was examined to see if this could predict response to treatment and to investigate if the drugs caused changes in thermal or mechanical sensibility.
The results shows that the intense pain, limited efficacy and tolerability of available treatments, the low overall rating of health, reduced work status and troublesome symptoms constitute a substantial impact on the quality of life for patients with peripheral neuropathic pain.
The NMDA-antagonist ketamine yielded substantial pain relief to patients with peripheral neuropathic pain and patients with neuropathic pain after spinal cord injury. However, the reported side effects limit the clinical usefulness of the treatment. Lidocaine did not give significant pain relief to the patients in the three studied groups. Morphine may represent a therapeutic alternative for some patients with central post-stroke pain, although only a small group of this category of patients responded with analgesia.
Assessment of baseline somatosensory functions could not be used to identify responders to treatment with either drug, nor did ketamine, lidocaine or morphine cause any changes in thermal or mechanical sensibility.
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Ramer, Matthew Stephen. "Sympathetic and sensory neuronal plasticity, peripheral substrates of neuropathic pain." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ31950.pdf.
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Kvarnström, Ann. "Neuropathic pain : quality of life, sensory assessments and pharmacological treatments /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3766.
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Kahlat, Karima. "Role in neuropathic pain of autoimmunity to myelin protein P0." Thesis, University of Bristol, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.544349.
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Moss, Andrew. "The role of VPAC2 receptors and PKA in neuropathic pain." Thesis, University of Edinburgh, 2002. http://hdl.handle.net/1842/29898.
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The role of the VPAC2 receptor in CCI was investigated. In VPAC2R (-/-) mice, the enhanced reflex responses to noxious heat and innocuous mechanical stimulation seen in wild type (WT) mice were attenuated. No morphological differences were seen between peripheral nerves of WT and VPAC2R (-/-) mice. Furthermore, intrathecal administration of a VPAC2R antagonist attenuated the enhanced reflex withdrawal responses to noxious heat and innocuous mechanical stimuli in WT mice following CCI, with no effect in VPAC2R (-/-) mice. In normal rats, intrathecal administration of PKA inhibitors attenuated the enhanced reflex withdrawal responses due to CCL. In situ hybridisation for isoforms of PKA regulatory (R) and catalytic (C) subunits showed a spinal increase in C-subunit, but not R-subunit mRNAs ipsilaterally at the peak of CCI sensitisation. Immunoblots confirmed an ipsilateral increase in C-subunits and showed a bilateral decrease in the RIβ subunit. The role of the proteasome in neuropathic sensitisation was studied. Electrophysiological recordings made from dorsal horn neurones in anaesthetised rats showed that proteasome inhibitors applied by ionophoresis inhibited activity evoked by innocuous brush and cold in CCI rats, while nociceptive responses were inhibited in CCI and normal animals. Intrathecal administration of proteasome inhibitors attenuated the enhanced paw withdrawal behaviours ipsilateral to CCI. The mRNA and protein levels for PGP 9.5 (a key enzyme is proteasomal function) were increased ipsilaterally. PKA enzymatic activity was increased in spinal cord ipsilateral to nerve injury and this increment was prevented by topical application of proteasome inhibitors. This investigation demonstrates the involvement of the VPAC2 receptor, the corresponding cAMP/PKA signal transduction cascade and the proteasome (a regulator of PKA activity) in the spinal sensitisation caused by CCI.
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Proudfoot, Clare W. J. "Analgesia mediated by the TRPM8 cold receptor in neuropathic pain." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/29953.
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To identify novel analgesic strategies for chronic pain, we investigated the phenomenon of analgesia produced by cutaneous cooling. The recent identification of specific cold sensory receptors has allowed, for the first time, investigation of the molecular mechanism underlying cooling-induced analgesia. We have shown that the cold-and-menthol receptor. TRPM8, is critically involved in cooling-induced analgesia. Activation of TRPM8 in a subpopulation of sensory afferents (by either cutaneous or intrathecal application of pharmacological agents or by modest cooling) elicits analgesia in neuropathic and other chronic pain models in rats, and inhibits the characteristic sensitisation of dorsal horn neurons that occurs ipsilateral to nerve injury. This analgesia is abolished following antisense knockdown of the TRPM8 receptor. In contrast, activation of the related putative cold-receptor TRPA1 produces hyperalgesia in naïve and neuropathic rats. TRPM8 expression was observed in small diameter sensory neurons in dorsal root ganglia and on afferent terminals in the spinal cord, with increases in specific subsets of sensory neurons following nerve injury. We further found that the central mechanism of TRPM8-mediated analgesia is mediated through inhibitory Group I/III metabotropic glutamate receptors, and is opioid-independent. These results identify TRPM8 as an essential molecular mediator of cooling-induced analgesia. We propose a novel analgesic axis in which activation of TRPM8-expressing afferents by innocuous cooling or chemical ligands leads to activation of inhibitory Group II/III metabotropic glutamate receptors in the spinal cord, which then exert inhibition over nociceptive inputs. These findings suggest that both TRPM8 and the inhibitory metabotropic glutamate receptors are promising targets for the development of novel analgesics for the treatment of neuropathic pain states.
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Wong, Shing Chau. "Treatment of neuropathic pain : by Chinese scorpion (Buthus martensii Karsch)." HKBU Institutional Repository, 2011. https://repository.hkbu.edu.hk/etd_ra/1439.
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Erichsen, Helle Kirstein. "Characterisation of the spared nerve injury model of neuropathic pain /." Cph. : The Danish University of Pharmaceutical Scienes, Department of Pharmacology, NeuroSearch, Kongl. Carolinska Medico Chirurgiska Institutet, 2003. http://www.dfh.dk/phd/defences/Hellekirsteinerichsen.htm.
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Bian, Di. "Peripheral and spinal mechanisms of neuropathic pain in the rat." Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/284087.
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The Chung peripheral nerve injury model shows consistent allodynia and thermal hyperalgesia, which represent the most common clinical neuropathic pain symptoms. Also clinically relevant, in the Chung model spinal morphine was inactive against tactile allodynia and diminished in potency in acute nociception without spinal/supraspinal antinociceptive synergy. Further, there are increased levels of dynorphin in multiple segmental regions of the spinal cord. This loss of spinal/supraspinal synergy and the spinal antiallodynic effect of morphine is restored by spinal MK-801 or antiserum to dynorphin. It is shown here that spinal transection blocks tactile allodynia, but not thermal hyperalgesia in Chung model rats, suggesting that thermal hyperalgesia involves both spinal and supraspinal circuits, whereas tactile allodynia depends on a supraspinal loop. The c-fiber specific neurotoxin resiniferatoxin before or after Chung surgery abolishes thermal nociception in Chung and sham-operated rats, but not allodynia in Chung model rats. These data suggest that tactile allodynia may be mediated by Aβ-fibers rather than c-fibers, offering a mechanistic basis for the observed insensitivity of allodynia to spinal morphine in Chung model rats. The data also show that PN3 sodium channel protein expression is increased in medium to large diameter neurons in the L4 ipsilateral DRG of Chung rats, and that selective knockdown of PN3 protein in the DRG with specific antisense prevents and reverses allodynia and hyperalgesia in Chung model rats without affecting normal nociceptive functions. Meanwhile, the increased dynorphin level in the spinal cord of Chung model rats returns to normal following spinal PN3 antisense. This suggests that increased PN3 protein in the DRG of Chung model rats may underlie an important mechanism for central sensitization and peripheral ectopic firing after nerve injury. Increased expression of PN3 is also found in the DRGs of diabetic and CFA model rats; knockdown of PN3 reverses allodynia and thermal hyperalgesia in these models. Together, these data suggest that relief from peripheral nerve injury, chronic inflammation, or diabetic neuropathy might be achieved by selective blockade of PN3. In light of the restricted distribution of PN3 to sensory neurons, such an approach might offer effective pain relief without a significant side-effect liability.
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Bashir, Farhat. "Determining diagnostic indicators for neuropathic pain in patients with osteoarthritis." Thesis, Curtin University, 2021. http://hdl.handle.net/20.500.11937/85465.
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This research aimed to differentiate neuropathic and inflammatory pain among osteoarthritis participants. Osteoarthritis participants were evaluated using self-report pain and function questionnaires, sensory and pain measures, proprioceptive function, MRI and biomarkers. Results indicated osteoarthritis participants had significant sensory deficit. 48% of participants were categorised as having neuropathic pain. A number of key measures were identified that can assist in diagnosing neuropathic pain. This information will be helpful in more effectively managing pain in osteoarthritis.