Les antidépresseurs ont un effet antiallodynique qui dépend de la stimulation des récepteurs β2-adrénergiques. Ceux-ci stimulent la production d’adénosine monophosphate cyclique (AMPc) régulé par les phosphodiestérases de type 4 (PDE4). Nous avons ici étudié l’effet d’inhibiteurs de PDE (iPDE) sur la douleur neuropathique, grâce à des approches de pharmacologie comportementale chez la souris complétées par de l’imagerie calcium et des approches moléculaires. Nos résultats montrent un effet antiallodynique des iPDE4 et des iPDE5. L’action des iPDE4 est liée à une diminution d’expression du TNFα dans le ganglion rachidien et au recrutement des récepteurs delta des opioïdes. Celle des iPDE5 nécessite à la fois les récepteurs mu et delta. Nous montrons aussi que l’action d’un iPDE4 dépend de la dose, l’activation de cellules gliales semblant corrélée à l’effet antiallodynique à faible dose, alors que celle des neurones à forte dose a un effet pronociceptif via les récepteurs TRPV1. / Antidepressants have an antiallodynic action that is dependent on β2-adrenoceptor stimulation. These receptors stimulate the cAMP production, which is regulated by type 4 phosphodiesterases (PDE4). Here, we studied that action of PDE inhibitors (iPDE) on neuropathic pain, using behavioral pharmacology approaches in mice, completed by calcium imaging and molecular approaches. Our results show the iPDE4s and iPDE5s have an antiallodynic action. The iPDE4s act through a decreased expression of TNFα in dorsal root ganglia and the recruitment of the delta opioid receptors. The action of iPDE5 requires both mu and delta opioid receptors. We also show that the action of an iPDE4 depends on the dose, the activation of glial cells at low dose being correlated with an antiallodynic action, while the recruitment of neurons at higher doses has a pronociceptive action via TRPV1 receptors.

Les douleurs neuropathiques sont secondaires à une maladie ou à une lésion affectant le système nerveux somatosensoriel et sont mal soulagées par les antalgiques usuels. Dans notre travail préclinique, nous avons étudié l’effet de différentes molécules, dont des antidépresseurs et antiépileptiques recommandés dans le traitement des douleurs neuropathiques. Dans un modèle murin de neuropathie traumatique, nous avons étudié l’influence de la période de traitement, précoce ou tardif, sur l’allodynie mécanique. Un traitement précoce par gabapentine ou par carbamazépine permet d’observer un effet préventif sur la chronicisation de l’allodynie. Dans un modèle murin de neuropathie diabétique, nous avons caractérisé l’action anti-allodynique d’un traitement par nortriptyline et par terbutaline. En clinique, nous avons réalisé un travail d’enquête rétrospective sur des patients opérés par thoracotomie. L’analyse des résultats montre une diminution significative du risque de présenter des douleurs chroniques avec des caractéristiques neuropathiques chez les patients traités par β2-agonistes au long cours. / Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system and is badly relieved by usual antalgics. In our preclinical work, we studied the effect of various molecules, in particular antidepressant and anticonvulsant drugs wich are recommended in the treatment of neuropathic pain. In a murine model of traumatic neuropathy, we studied the influence of the period of treatment, early or late, on the mechanical allodynia. An early treatment with gabapentin or carbamazepine leads to a preventive effect on sustained allodynia. In a murine model of diabetic neuropathy, we characterized the antiallodynic action of nortriptyline and terbutaline. In our clinical work, we realized a retrospective survey on patients operated by thoracotomy. The analysis of the results show a significant decrease of the risk to suffer from chronic pain with neuropathic characteristics in patients treated with long-term β2- agonists.

Les douleurs neuropathiques, celles qui sont provoquées par des lésions du système nerveux central ou périphérique, sont les plus difficiles à traiter du fait de leur résistance aux traitements antalgiques classiques. Les traitements utilisés aujourd’hui font appel à des classes thérapeutiques non spécifiquement ciblées sur la douleur, en particulier des antidépresseurs et des anticonvulsivants. Leur efficacité limitée ne repose en fait que sur des observations empiriques. Une meilleure connaissance des processus physiopathologiques sous-tendant les douleurs neuropathiques constitue un préalable à toute innovation thérapeutique, et c’est à cette fin que je me suis appliqué à développer deux modèles de douleurs neuropathiques chez le rat pour en étudier les caractéristiques comportementales, fonctionnelles, cellulaires et biochimiques. Le premier modèle visait à l’induction d’une douleur neuropathique centrale provoquée par la section complète de la moelle épinière au niveau thoracique (T8-T9) ; le second a consisté à injecter, directement au niveau spinal, par voie intrathécale (i.t.), le facteur neurotrophique BDNF (Brain Derived Neurotrophic Factor ; dont l’implication dans les voies de signalisation nociceptive est bien établie dans la littérature). Dans les deux cas, les conséquences pro-algiques de ces interventions ont été comparées à celles induites par la ligature unilatérale du nerf sciatique, qui constitue encore aujourd’hui un modèle classique, mais très imparfait, d’une douleur neuropathique périphérique. Dès le 2ème jour après la section spinale, et jusqu’au moins deux mois plus tard, les rats lésés présentent une forte allodynie mécanique (test des filaments de von Frey) dans le territoire cutané juste en avant de la lésion. Cet effet traduit bien une neuropathie centrale car il n’existe pas chez les rats « sham » qui ont subi l’intégralité de l’intervention chirurgicale à l’exception de la section spinale. L’allodynie mécanique est associée à une induction significative de l’expression (RTqPCR) de marqueurs de souffrance neuronale (ATF-3) et d’activation microgliale (OX-42, récepteurs P2X4, P2X7 et TLR4) et astrocytaire (GFAP), ainsi que du BDNF et de cytokines pro-inflammatoires (IL-1ß, IL-6, TNF-α), mais de façon plus transitoire, ceci dans les ganglions de racines dorsales et/ou la moelle épinière dorsale (comme à la suite de la ligature du nerf sciatique, mais avec des cinétiques différentes). Pour sa part, l’injection intrathécale i.t. d’une dose infra-nanomolaire unique de BDNF (0.3 – 3.0 ng) induit aussi une forte allodynie et une hyperalgésie mécaniques, au niveau des pattes postérieures, qui se développent en 3-5 jours, et perdurent pendant deux semaines. Cependant, au contraire de la section spinale (et de la ligature du nerf sciatique), l’injection i.t. de BDNF ne provoque pas d’activation microgliale ni d’induction de cytokines. Elle entraine en revanche une auto-induction du BDNF, qui semble clé pour l’hyperalgésie puisque celle-ci peut être, en grande partie, supprimée par l’administration d’un inhibiteur du récepteur TrkB du BDNF, la cyclotraxine B (20 mg/kg i.p.), comme d’ailleurs l’hyperalgésie induite par la ligature du nerf sciatique. Au plan pharmacologique, un antalgique opiacé comme le tapentadol s’est révélé efficace dans les deux modèles. De même, les anticonvulsivants, comme la prégabaline et la gabapentine, ont réduit la douleur neuropathique chez les rats injectés par le BDNF i.t. et chez les rats CCI-SN. En conclusion, il semble que l’injection intrathécale de BDNF, qui évite la réalisation de lésions par intervention chirurgicale, puisse constituer un nouveau modèle pertinent de douleur neuropathique chez le rat. De plus, nos résultats laissent à penser que le blocage de la voie de signalisation BDNF-TrkB pourrait ouvrir de nouvelles pistes pour la réduction des douleurs neuropathiques périphériques. (...) / Neuropathic pain, caused by lesions of central or peripheral nervous system, is difficult to treat because of its resistance to classical antalgic treatments. Most of pharmacotherapeutic treatments of neuropathic pain (antidepressants, anticonvulsants) currently used are only based on empirical data and are not specifically aimed at relieving pain. Better knowledge of the mechanisms underlying neuropathic pain is an absolute prerequesite to develop new and innovative treatments. With the aim of contributing to elucidate these mechanisms, I developed two models of neuropathic pain in rats, and studied their behavioral, pharmacological, cellular and biochemical characteristics. The first model consisted of the induction of central neuropathic pain by complete transection of the spinal cord at T8-T9 level. The second one consisted of the administration of BDNF (Brain Derived Neurotrophic Factor; which implication in nociceptive signaling pathways is well established in the literature), directly at the spinal level, via intrathecal (i.t.) injection. In both cases, pro-algesic consequences of these interventions have been compared to those induced by unilateral ligation of the sciatic nerve, which is still considered as a classical, although not really satisfactory, model of peripheral neuropathic pain. From the second day after spinal cord transection up to (at least) 2 months later, lesioned rats developed a strong mechanical allodynia (von Frey filaments test) within a limited cutaneous territory just rostral to the surgical scar. This effect really reflected central neuropathic pain because it did not occur in control, « sham operated » animals, that underwent the same surgical intervention except the spinal cord transection. Mechanical allodynia was associated with marked overexpression of markers of neuronal injury (ATF-3), microglial activation (OX-42, P2X4, P2X7 and TLR4 receptors), astrocyte activation (GFAP), as well as upregulation of transcripts encoding BDNF and pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α, but only transiently for the latter cytokine), in dorsal root ganglia and/or spinal cord. Therefore, spinal cord transection triggered a strong neuroinflammatory reaction, like that occurring after peripheral nerve lesion, but with different time course and amplitude. On the other hand, intrathecal injection of an infra-nanomolar dose of BDNF (0.3 – 3.0 ng) also induced a strong mechanical allodynia and hyperalgesia at hindpaw level, which developed within 3-5 days and lasted for at least two weeks. However, in sharp contrast with spinal cord transection (and sciatic nerve ligation), i.t. injection of BDNF did not induce any microglial activation and/or proinflammatory cytokines upregulation. Intrathecal (exogenous) BDNF-induced (endogenous) BDNF auto-induction might play a key role in the maintenance of i.t. BDNF-induced hyperalgesia as the latter can be reversed by pharmacological blockade of the BDNF receptor TrkB (with cyclotraxin B at 20 mg/kg i.p., which also reversed sciatic nerve ligation-induced hyperalgesia). Pharmacological investigations showed that the opioid antalgic drug tapentadol and anticonvulsants such as pregabalin and gabapentin efficiently reduced neuropathic pain in i.t. BDNF i.t. as well as in sciatic nerve-ligated rats. Accordingly, intrathecal injection of BDNF might represent a new non-surgical model of neuropathic pain in rats. Moreover, our results indicate that blockade of BDNF-TrkB signaling could open new therapeutic perspectives for alleviating peripheral neuropathic pain. This innovative pharmacological approach should also be explored in the case of central neuropathic pain caused by spinal cord injury.

Les neuropathies des petites fibres (NPF), ou neuropathies douloureuses, se caractérisent par des douleurs neuropathiques et une dysautonomie, symptômes particulièrement invalidant et dont la prise en charge thérapeutique actuelle n’est pas satisfaisante. La biopsie cutanée, actuel examen « gold standard » dans le diagnostic des NPF, est un outil intéressant du fait de sa simplicité de réalisation sans séquelle, et de son accessibilité. Cependant, son interprétation actuelle est limitée, n’apportant qu’une information quantitative sur l’existence ou non d’une perte en fibres intra-épidermiques, résultante des NPF plus qu’une explication de la symptomatologie. Dans une première étude nous avons comparé la quantification des fibres de la biopsie cutanée à leur analyse fonctionnelle explorée par le SUDOSCAN®, ne retrouvant qu’une faible corrélation entre les deux outils et confirmant le mauvais reflet de la fonctionnalité des fibres dans la biopsie cutanée. De plus, dans une deuxième étude sur les patients Charcot-Marie-Tooth 1A, nous n’avons pas mis en évidence de corrélation entre la biopsie cutanée et les symptômes (sauf la sensibilité à la piqûre), soulignant une nouvelle faiblesse de cet examen. Concernant les biomarqueurs cutanées, l’analyse des cellules de Langherans dans différentes neuropathies a retrouvé une augmentation de celles-ci chez les patients diabétiques et une densité plus faible chez les sujets sains, mais également une diminution chez le patient CMT1A, sans jamais aucune corrélation avec la densité des petites fibres. Enfin, dans une troisième partie étudiant le syndrome POEMS, nous avons mise en évidence que la vascularisation cutanée, significativement plus élevée dans le POEMS, serait un biomarqueur candidat intéressant à visée diagnostique étiologique. La recherche de biomarqueurs cutanés, afin d’augmenter la puissance diagnostique, de mieux comprendre la physiopathologie de la perte en fibres pour de trouver des cibles thérapeutiques et améliorer la prise en charge de ces patients, parait essentielle. Des études supplémentaires sont nécessaires, et certaines sont en cours dans la continuité de ce travail. / Small-fiber neuropathies (SFN), or painful neuropathies, are characterized by neuropathic pain and autonomic dysfunction, which are particularly disabling symptoms and whose current therapeutic management is not satisfactory. The skin biopsy, which is the "gold standard" in the SFN diagnosis, is an interesting easy to do and accessible. However, its current interpretation is limited, bringing only a quantitative information: there is a loss of intraepidermic nerve fibers, resulting from SFN more than an explanation of the symptomatology. In a first study, we compared the quantification of skin biopsy fibers with their functional analysis explored by SUDOSCAN®. We found a weak correlation between the two tools, confirming that skin biopsy is not a good reflet of fibers function. Nevertheless, in a second study on Charcot-Marie-Tooth 1A patients, we found a correlation between cutaneous biopsy and sensitivity to sting, sensitivity transmitted by small fibers. Regarding cutaneous biomarkers, analysis of Langherans cells in different neuropathies found an increase in these in diabetic patients and a lower density in healthy subjects, but also a decrease in patients affected with CMT1A, without ever having any correlation with small nerve fibers density. Finally, in a third part studying the POEMS syndrome, we found that the dermal vascularization, which is significantly higher in POEMS, would be an interesting candidate biomarker for etiological diagnostic purposes. The search for skin biomarkers to improve the diagnosis and to better understand the pathophysiology of fiber loss in order to find therapeutic targets to improve the management of these patients seems essential. Additional studies are needed, and some are ongoing as a continuation of this work.

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.

Title: The Possibilities of Influencing the Neuropathic Pain via Virtual Reality in Incomplete Spinal Cord Injury Patients. Objectives: The goal of this thesis is to determine how a long-term exposure to virtual reality affects experiencing neuropathic pain in the case of patients with incomplete spinal cord lesions. Methods: The study included 8 probands (3 females and 5 males) aged from 30 to 64 years (average age 49.5 ± 12.0 years) from among the clients of a charitable trust "Centrum Paraple". At the entrance examination, the participants received a pair of VR BOX VR-X2 virtual reality headsets enabling viewing of two-dimensional (2D) videos in the three-dimensional (3D) format. Thereafter they were watching, in their home environment, varied therapeutic videos depicting "virtual walking" - human walking viewed from a first person perspective. After 3 months of therapeutic intervention, a follow-up examination was carried out to determine the effect of the therapy. The Neuropathy Pain Scale and the International Spinal Cord Injury Pain Basic Data Set were used to assess changes in the perception of neuropathic pain. The results were statistically processed by means of a paired t-test in the R program. To monitor objective changes in the somatosensory and motor nervous systems, the evoked...

Patient nonadherence to physicians' prescribed therapeutic regimen is the greatest challenge in the effective treatment of patients with diabetes worldwide. Scientific evidence has revealed that nonadherence to prescribed medication could result in diabetic complications such as cardiovascular disease, retinopathy, nephropathy, and neuropathic diabetic foot ulcers. The purpose of this study was to explore predictive relationships between levels of adherence to antidiabetic medications, patient HbA1c levels, and diabetic complications among Jamaicans, an understudied population. The research question that guided this study was: Do the patient level of adherence and HbA1c levels have any predictive relationship with the severity of diabetic complications (cardiovascular disease, retinopathy, nephropathy and neuropathic foot ulcer) among Jamaicans after controlling for age and gender? The theory of planned behavior was used to guide the study. Data regarding diabetic complications were collected from 119 records during a cross-sectional review of patient dockets. Level of adherence was determined from an interviewer-administered Morisky 8-item adherence scale. A multiple regression analysis revealed that lower levels of patient adherence to treatment and higher HbA1c levels predicted greater severity of cardiovascular disease (p = .000; p = .000), retinopathy (p = .009; p =.090), nephropathy (p =.007; p =.001) and diabetic neuropathic foot ulcers (p =.027; p =.001). Findings from this study will contribute to the knowledge base on diabetic medication nonadherence and may encourage health care professionals to advocate for better medication adherence strategies among people with diabetes.

No description available.

Trigeminal neuralgia is a painful neuralgia with a complicated pathology that is not clearly understood. Due to the ambiguity of the condition, patients often have to search for medical providers that specialize in trigeminal neuralgia, and even with the guidance of a specialist, some patients do not respond well to treatment.1 Despite the uncertainty surrounding the specifics of the disease, there are treatments available that can provide some level of pain relief for patients suffering from this disorder. When a patient does not respond well to medical therapy, surgery can be the next appropriate step in patient care management.2 However, while surgery can provide significant pain relief for patients who qualify, non-surgical treatments are needed during the interim, in the event of relapse, or for individuals who do not qualify for surgery. Cognitive behavioral therapy (CBT) is a well-researched treatment for chronic pain resulting from various diseases and disabilities.3 A systematic literature review was performed to identify if CBT decreases pain and improves the quality of life for patients diagnosed with classical, secondary, or idiopathic trigeminal neuralgia. More research is needed, but there is promising evidence in the literature that cognitive behavioral therapy can be useful for patients with trigeminal neuralgia to help them cope with their pain. In addition, there may be evidence that, while somewhat effective alone, cognitive behavioral therapy may be more effective in conjunction with another treatment such as medication. These results are encouraging for patients suffering with the chronic pain of trigeminal neuralgia, and future studies should further investigate the benefits of cognitive behavioral therapy for patients with trigeminal neuralgia.

No description available.