There was few human study evaluated the analgesic effect of acupuncture on central nervous system (CNS). The electrical temporal summation (TS) pain model has been validated and provides the opportunity to study the central inhibition effect of acupuncture in healthy humans. The present study aimed to: 1. systematically review available randomised, controlled trials (RCTs) of acupuncture on experimentally induced pain in healthy humans; 2. conduct a RCT to assess the effect of manual acupuncture (MA) and electro-acupuncture (EA) on TS of pain and the spatial (i.e. the local and remote sites to acupuncture stimulation) and the temporal (i.e. immediately after and 24-hours after the intervention) characteristics of this effect. The systematic review was carried out in accordance with the requirements of a Cochrane Systematic Review. The methodological quality and credibility of the acupuncture intervention of the included RCTs were assessed. The Review Management software (RevMan version 4.2, The Cochrane Library) was used for data extraction and data analysis. 605 papers were identified from four databases (Pubmed, Cochrane Library, CINAHL and EMBASE). Only nine papers met the inclusion criteria. The methodological quality and credibility of the acupuncture invention were satisfactory. The pain models and interventions applied varied substantially from study to study. Consequently, meta-analyses were not conducted. Comparing acupuncture with non-invasive control, significant acupuncture analgesia was reported. These studies also demonstrated that invasive controls produced analgesia. For the RCT of acupuncture on TS, 27 healthy volunteers were recruited and randomly assigned to either EA, MA or sham-acupuncture (SA) group, with nine volunteers in each group. To test pain thresholds, transcutaneous electrical stimulation was delivered to two sites on the anterior aspects of both legs and one site on the dorsum of the non-dominant forearm. Pain thresholds to single electrical stimulation (SPT) and to TS stimulation (TST) were assessed before, 30-minutes after and 24-hours after the intervention. Acupuncture was given to Zusanli (ST36) and Fenglong (ST 40) on the dominant leg. The level of anxiety was assessed before and after acupuncture with Spielberg State and Anxiety Inventory. The three groups were comparable at baseline. The level of anxiety did not change significantly after acupuncture. EA significantly increased SPT and TST on the treatment leg 24-hour after the treatment when compared with SA (p less than 0.05), but did not increase those measured on the non-treatment leg or the forearm. The fact that such an effect increased within 24 hours after acupuncture might indicate the potential role of neurohumoral mechanisms in acupuncture analgesia. The analgesia effect of EA on TS tended to be localised at the needling site. This observation is different from the understanding of the wide-spread effect of acupuncture. The discrepancy could be due to the small sample size of the current study. In conclusion, this is the first study that demonstrates EA elicits a strong inhibition on the CNS in health humans. Such a central effect lasts more than 24 hours, and limits to the site where acupuncture is applied. These findings need to be confirmed in other TS models.

Chronic neuropathic pain affects up to 8% of the United Kingdom population and is a difficult condition to manage. It is established and maintained through many mechanisms, including central sensitisation (CS) in the spinal cord and brainstem. Neuropathic pain manifests as spontaneous pain, sensory loss and evoked hypersensitivity. The development of novel treatments for neuropathic pain is challenging, in part due to inadequate experimental models of clinically relevant pain. The use of functional magnetic resonance imaging (fMRI) techniques for imaging acute and increasingly tonic states enables the assessment of the neural correlates of evoked hypersensitivity and persistent pain, with the goal of developing appropriate biomarkers to test new therapies. This thesis develops novel techniques for the assessment of ongoing pain states and their modulation by therapies. We first identified a suitable human experimental model of CS using topical capsaicin, and an fMRI pipeline for the investigation of supraspinal involvement in pain hypersensitivity. In a placebo-controlled study, we then demonstrated the improved sensitivity of fMRI above subjective reports in detecting the efficacy of a known analgesic as compared to an ineffective active compound in a small cohort. To translate this to the more clinically relevant symptom of spontaneous pain, we developed and validated the use of a multi-inversion time pseudo-continuous arterial spin labelling (ASL) imaging and analysis pipeline for the neural assessment of tonic states and the absolute quantification of cerebral blood flow (CBF). Current evidence from structural and functional studies suggests a direct role for the posterior insula cortex in the encoding of nociception and pain. Using the ASL pipeline, we found that only a CBF change in the posterior insula region was correlated with the changing perception of persistent capsaicin-induced pain, and in a separate experiment showed that suppression of CBF in this region by gabapentin was related to the drug's suppression of subjective pain perception. We also demonstrated in a cohort of phantom limb patients that pain relief resulting from transcranial direct current stimulation of the deprived sensorimotor cortex is neurally represented by a decrease in posterior insula CBF. In a separate study, we showed that baseline CBF in the periaqueductal grey can predict individuals who are most vulnerable to pain and hypersensitivity following the induction of capsaicin-related CS. Taken together, these findings suggest that fMRI can be used as a tool to assess the efficacy of established and novel analgesics, with the midbrain reticular formation and posterior insula cortex being prime candidates as biomarkers of CS mechanisms and persistent pain respectively. Relatedly, ASL-fMRI may also be an effective technique for evaluating individuals' susceptibility to pain following inflammation or injury.

La prévalence de l’arthrose féline augmente fortement avec l’âge atteignant plus de 80% des chats de plus de 11 ans. L'arthrose induit une douleur chronique s’exprimant par des changements de comportements et une diminution de la mobilité. Il n'existe aucun outil validé pour évaluer la douleur chronique associée à l’arthrose chez le chat. Conséquemment, aucun traitement ciblant cette douleur n’a pu être validé. Notre hypothèse de recherche est que la douleur arthrosique chez le chat induit des handicaps fonctionnels, des changements neurophysiologiques et un état d'hypersensibilité qu'il faut évaluer pour quantifier de manière fiable cette douleur et ses répercussions sur la qualité de vie de l'animal. Nos objectifs étaient 1) de développer des outils adaptés aux chats mesurant les handicaps fonctionnels grâce à des outils cinématiques, cinétiques et de suivi de l'activité motrice ; 2) de caractériser les changements fonctionnels et neurophysiologiques secondaires à la douleur arthrosique et de tester avec ces outils un traitement analgésique à base d'anti-inflammatoire non stéroïdien ; 3) de développer une technique adaptée aux chats pouvant caractériser la présence du phénomène de sensibilisation centrale à l'aide d'une évaluation de la sommation temporelle mécanique ; 4) de tester la possibilité de mesurer le métabolisme glucidique cérébral par tomographie d’émission par positrons comme marqueur des changements supraspinaux secondaires à la chronicisation de la douleur. Grâce au développement d’outils de mesure de douleur chronique objectifs, sensibles et répétables nous avons caractérisé la douleur chez les chats arthrosiques. Ils présentent des signes de boiterie quantifiée par une diminution de l’amplitude de l’articulation ou par une diminution de la force verticale d’appui au sol et une diminution de l’activité motrice quotidienne. Ces deux derniers outils ont permis de démontrer qu’un anti-inflammatoire non stéroïdien (le méloxicam) administré pendant quatre semaines réduit la douleur arthrosique. De plus, grâce au développement de tests sensoriels quantitatifs et à l'utilisation d'imagerie cérébrale fonctionnelle, nous avons démontré pour la première fois que la douleur arthrosique conduisait à des modifications du système nerveux central chez le chat. Particulièrement, les chats arthrosiques développent le phénomène de sensibilisation centrale mis en évidence par un seuil de retrait aux filament de von Frey diminué (mesure réflexe) mais aussi par une facilitation de la sommation temporelle mécanique (mesure tenant compte de la composante cognitive et émotionnelle de la douleur). L'augmentation du métabolisme cérébral dans le cortex somatosensoriel secondaire, le thalamus et la substance grise périaqueducale, souligne aussi l'importance des changements liés à la chronicisation de la douleur. Un traitement analgésique adapté à l’arthrose permettra d’améliorer la qualité de vie des chats atteints, offrira une option thérapeutique valide aux praticiens vétérinaires, et profitera aux propriétaires qui retrouveront un chat actif et sociable. La découverte de l'implication du phénomène de sensibilisation central combiné à l'investigation des changements cérébraux secondaires à la douleur chronique associée à l'arthrose par imagerie fonctionnelle ouvre de nouvelles avenues de recherche chez le chat (développement et/ou validation de traitements adaptés à l'état d'hypersensibilité) et les humains (potentiel modèle naturel de douleur chronique associée à l'arthrose). / Feline osteoarthritis prevalence increases with age, up to 80% in cats aged 11 years old and more. Osteoarthritis is associated with chronic pain expressing as altered behaviour and a decrease in mobility. Currently, there is no validated technique to evaluate osteoarthritis-associated chronic pain in cats. This situation leads to an absence of approved medication for the treatment of OA-associated chronic pain in cats. Our hypothesis states that osteoarthritis-associated pain in cats is expressed as physical disabilities, neurophysiologic changes, hypersensibility, which need to be assessed to quantify adequately this pain and its impact on quality of life. Our objectives were 1) to develop a cat adapted method to assess physical disabilities using kinematics, kinetics and motor activity evaluations; 2) to describe functional and neurophysiologic changes related to osteoarthritis-associated pain, and to test a non steroidal anti-inflammatory based analgesic treatment; 3) to develop a cat adapted method to detect central sensitisation using mechanical temporal summation; 4) to test the feasibility of measuring carbohydrate brain metabolism using positron emission tomography as a marker of supraspinal changes-associated with pain chronicity. Using objective chronic pain evaluation tools determined as sensitive and repeatable, we characterized feline osteoarthritis-associated pain. Cats afflicted with osteoarthritis presented lameness characterised by decreased joint amplitude, or decreased peak ground reaction vertical force, and decreased motor activity. Using the two latter tools, we demonstrated the efficacy of a non steroidal anti-inflammatory (meloxicam) to alleviate osteoarthritis-associated pain after four weeks of administration. Moreover, using quantitative sensory testing and brain functional imaging, we demonstrated for the first time, that osteoarthritis-associated pain in cats led to central nervous system changes. Specially, cats afflicted with osteoarthritis developed central sensitisation as indicated by a decreased von Frey withdrawal threshold (a reflex evaluation), and also by a facilitated mechanical temporal summation (an approach allowing to take into account affective and cognitive dimensions of pain). The increase of brain metabolism in the secondary somatosensory cortex, thalamus and periaqueductal grey matter also highlighted the importance of pain chronicity related changes. Using an analgesic treatment built to alleviate osteoarthritis-associated pain will improve cats quality of life, will help veterinarians, and will benefit owners who will retrieve an active and social cat. Demonstrating both the importance of central sensitisation and assessment of brain changes related to osteoarthritis-associated chronic pain using brain functional imaging opens new research opportunities in cats (development and/or validation of hypersensitivity related treatments), and humans (potential natural model of osteoarthritis-associated pain).