Neuropathic pain is becoming a disease of global burden with growing prevalence worldwide. It is difficult to treat and there is no assured cure for it so far. Patients have to live with it relying on combinations of drug treatments to ameliorate the effect. The cause of neuropathic pain is often considered as a dysfunction of the nervous system which involves both peripheral and central nervous system sensitization. However, the mechanism behind it remains poorly understood at the molecular level. In my thesis, I have investigated Endothelin-1 (ET-1), a potent vasoconstrictor and neuro-modulator, in the central pain-process in neuropathic pain. ET-1 induction has been reported in a variety of pathological states such as cancer, ischaemia, and neuropathic pain. The effect of central endogenous ET-1 in development of neuropathic pain has not been adequately studied. Therefore, in my first study, I evaluated the influence of endogenous ET-1 in neuropathic pain by antagonizing Endothelin Receptor type A (ETAR), which is documented as the receptor that ET-1 acts on to induce pain, in the CNS. BQ-123, an ETAR selective antagonist, was administered intrathecally to study the effect of central ET-1 in neuropathic pain induced by Peripheral Sciatic Ligation (PSL) in Sprague Dawley (SD) rat. I found that repeated administration of BQ-123 alleviated mechanical allodynia, which developed after PSL as a typical symptom of neuropathic pain. Thus, ET-1 and ETAR may involve in PSL- induced neuropathic pain. To the best of our knowledge, exogenous administration of ET-1 in the CNS has been shown to exert a pain-inhibiting effect in thermal and inflammatory pain, but the mechanism and the cellular origin of such pain-inhibiting nature remains elusive. Hence, I further investigated the effect of central ET-1 in neuropathic pain. Here, transgenic mouse overexpressing ET-1 in astrocytes (GET-1) was used as a model. I found that GET-1 mice exhibited 15-fold of ET-1 mRNA induction in the spinal cord by real-time PCR. However, GET-1 transgenic mice did not show altered mechanical threshold compared to non-transgenic (Ntg) mice at basal level under physiological condition. After PSL, I found that GET-1 transgenic mice did not show signs of neuropathic pain while age-matched Ntg mice had mechanical allodynia. High expression of ETAR observed only in Ntg mice after PSL supports the pain-alleviating effect of ETAR antagonist shown in our first study. Moreover, I explored the relationship between ET-1 and glial glutamate transporter EAAT2 which is responsible for major clearance of glutamate in the CNS. Interestingly, high expression level of EAAT2 was observed distinctively in GET-1 transgenic mice which did not develop PSL-induced neuropathic pain. Thus, EAAT2 may be the key factor in neuron protection from central sensitization by enhanced glutamate release in induction of neuropathic pain. These results suggest that endogenous central ET-1 may mediate neuropathic pain partially via ETAR. Taken together with the evidence that GET-1 did not develop neuropathic pain and showed high expression of EAAT2, I concluded that overexpressed astrocytic ET-1 in GET-1 mice exerted an analgesic effect in neuropathic pain by modulating expression of EAAT2. / published_or_final_version / Anaesthesiology / Master / Master of Philosophy

This thesis deals with a potential interaction between the vestibular system and the phenomenon of central pain.  I provide behavioural and magnetoencephalographic (MEG) evidence that cold caloric vestibular stimulation (CVS) can alleviate central pain in some sufferers. I argue that activation of the parieto-insular vestibular cortex (PIVC) in central pain patients can act via the parabrachial nucleus in the brainstem to rebalance the integration of thermosensory input and suppress the perception of pain at the anterior cingulated cortex (ACC).  This is consistent with the thermosensory disinhibition hypothesis, which proposes that central pain is a thermoregulatory disorder which results from the loss of the central inhibition of pain by cooling.  I go on to propose that the PIVC and anatomically adjacent interoceptive cortex in the dorsal posterior insula (dpIns) share a number of similarities and that PIVC is best viewed as part of a wider interoceptive system. Based on the MEG data I suggest that low threshold C mechanoceptors may play a role in tactile allodynia in central pain.  I also use the MEG data to propose that the disruption of interoceptive input to the dpIns could lead to tactile afferents priming the primary motor cortex to respond more rapidly to subsequent ACC activation.  This effect may be mediated via a corollary branch of interoceptive input that runs not to the dpIns but to the fundus of the central sulcus. The final chapter contains additional research into the issue of body image, via investigations into apotemnophilia.  I provide MEG and other evidence suggesting that it is a disorder of the right parietal lobe.  I then propose a neurological explanation for a condition previously thought to be entirely psychological.

No description available.

La douleur neuropathique centrale est une affection fréquente dont le traitement est complexe. En raison d’un important taux de résistance aux traitements pharmacologiques, des techniques de neuromodulation ont été développées. Parmi elles, on retrouve les stimulations du cortex moteur primaire (ou gyrus précentral), invasive (i.e. stimulation électrique épidurale, eMCS) et non-invasive (i.e. stimulation magnétique transcrânienne répétitive, rTMS). Ces techniques restent limitées par différents paramètres. La rTMS a principalement été étudiée à travers des séances uniques, et son efficacité comme moyen thérapeutique au long cours reste mal connue. La eMCS souffre d’un manque de prédicteurs individuels d’efficacité suffisamment robustes pour sélectionner à bon escient les candidats à la chirurgie. Enfin, le cortex moteur primaire est une cible de découverte empirique, et d’autres cibles sont à envisager pour améliorer les résultats de ces neuromodulations corticales. Notre travail avait pour objectif l’amélioration des connaissances vis à vis de ces différentes limites. Il s’est articulé autour de 3 axes principaux :- L’étude de la rTMS en séances répétées, au long cours, comme moyen thérapeutique à part entière. - L’étude de la rTMS en séances répétées comme moyen de prédiction de la réponse antalgique à la eMCS.- Le développement de méthodes permettant la localisation fiable et reproductible du cortex pré-frontal dorsolatéral comme cible alternative de stimulation. / Central neuropathic pain is a frequent and hard to treat condition. Because of a large amount of drug-refractoriness, neuromodulation techniques have been developed. Among them, the mostly used is motor cortex stimulation, which can be both invasive (epidural motor cortex stimulation (eMCS)) and non-invasive (repetitive magnetic transcranial stimulation (rTMS)). These techniques remain limited by different problems: On one side, rTMS has been mainly studied through unique session practice and its use for pain therapy in a long-term scale remains not well understood. On the other side, eMCS suffers from a lack of predictability: A great proportion of patients present an insufficient relief, making eMCS less and less used. Finally, the motor cortex target is a chance discovery, and some other targets could be intended to improve the results. This work had the increase of knowledge about cortical stimulations as a main goal, especially about their different limitations. This work concentrated on 3 aims: - The study of chronic, repeated sessions of rTMS, used as a long-term tool for pain therapy. - The study of repeated rTMS sessions to predict eMCS.- The development of reliable tool to help to localize others cortical targets.

The general aim of this thesis was to classify and describe long-term pain two years after a stroke and to describe the experiences of pain, and the consequences it has on the persons’ lives. The studies were conducted from a multidimensional perspective on pain, combining quantitative and qualitative methods. Three types of long-term pain were classified and described among the 43 participants included, aged 33-82 years. These were central post-stroke pain, nociceptive, mainly shoulder pain, and tension-type headache. Pain onset, within one to six months in most of the cases was after discharge from the hospital. Continuous pain or pain almost every day was reported by nearly two-thirds. The pain was mostly described as troublesome, annoying and tiring in all pain groups. The rating of pain intensity revealed individual differences among the participants within the pain groups. In addition to long-term pain, the participants suffered several impairments and nearly half of them were dependent on others, and two-thirds on assistive devices. Several coping strategies were described, most often problem-focused. Their health-related quality of life was decreased, mostly related to their long-term pain and physical impairments. Their experiences of caring revealed the need of improvements in knowledge about longterm pain, attention and understanding among the professionals, and continuity in the contacts. / On the day of the public defence the status of article III was: Accepted for publication and the status of article IV was: In press.