ANIMAL MODELS FOR OA PAIN RESEARCH AND DRUG DISCOVERY

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    18-Sep-2016

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    INFLAMMATORY AND NEUROPATHIC PAIN: NEWINSIGHTS INTO GENETIC DETERMINANTSS.B. McMahonKings College London, London, United KingdomPurpose: Pain sensitivity is known to vary considerably betweenpeople. This is true both for experimental pain, for instancewhere a standard force is applied to normal healthy tissue, butalso for disease-related pain where osteoarthritis (OA) providesa particularly good example. It has long been recognised up to50% of individuals with radiographic indications of OA disease donot report pain, and there is a poor correlation between pain anddegree of radiographic change in OA. The inuence of heritable(genetic) factors on pain sensitivity in general and OA pain inparticular will be reviewed in this talk.Methods: Results: Mutations in a few individual genes haverecently been demonstrated to have a dramatic effect on painappreciation. The best known example is mutations in the trkAgene, a number of which of lead to the development of congeni-tal insensitivity to pain with anhydrosis (also know as hereditarysensory neuropathy type IV). These mutations lead to a failure ofsmall diameter nociceptive neurones to develop. More recentlymutations in a sodium channel gene normally expressed selec-tively in peripheral pain sensitive neurones (so-called Nav 1.7)have also been found to lead to both loss of function (congenitalanalgesia) and gain of function (erythromelagia) phenotypes.Wehave recently undertaken a classical twin study to evaluate therelative contributions of genetic and environmental factors on re-sponses to painful stimuli in human volunteers to a wide varietyof pain traits. Statistically signicant genetic components (varyingbetween 22-55%) were seen for the responses to the majority ofpainful stimuli including sensitivity to heating the skin, areas ofsecondary hyperalgesia brush evoked allodynia following a burninjury and iontophoresis of acid solutions.Conclusions:Our study demonstrates the importance of geneticfactors in determining human experimental pain sensitivity, andopens the way for its use as a phenotype in gene discovery.Since experimental pain sensitivity is known to be a predictorfor pathological pain, our data imply that genetic factors have animportant aetiological contribution towards clinical pain states.

    ANIMAL MODELS FOR OA PAIN RESEARCH AND DRUGDISCOVERYJ.L. HenryMcMaster University, Hamilton, ON, CanadaPurpose: To address mechanisms underlying pain in an animalmodel of OA.Methods: We have determined the effect of surgically-inducingderangement of one knee in the rat on properties of spinal andperipheral sensory neurons using single neuron electrophysio-logical recording.Results: Mankin scoring of the joint in model rats over a vemonth period revealed progressive development of OA pathol-ogy. Articulation of the deranged knee in model but not sham-operated or nave animals induced a brief hetero-segmentalpro-nociceptive effect in the tail ick test. In a modied open eldtest model rats were less active than sham-operated or naverats, suggesting a decrease in voluntary use of the joint. Testsof mobilization on a slowly rotating drum conrmed that this de-

    crease was not due to a reduction of the mechanical viability ofthe joint.To assess the properties of spinal dorsal horn wide dynamicrange (WDR) neurons, single neuron in vivo electrophysiologyexperiments were carried out. A signicantly greater percent-age of these neurons from model animals had spontaneousdischarge rates < 1 spike per sec. Furthermore only neuronsfrom model animals exhibited an increase in discharge rate anda modulation of the pattern of spontaneous discharge followingarticulation of the knee. Articulation of the deranged knee alsoreduced the heterogeneity of the discharge patterns observed inresponse to touch and pinch stimuli. This decreased responserange to non-noxious vs. noxious stimuli was accompanied byan articulation-induced increase in the number of low-thresholdspike (LTS) bursts exhibited by neurons that responded to sub-stance P. We propose that the pro-nociceptive effect of articula-tion is due in part to a change intrinsic to the WDR neurons thatmodulates sensitivity to innocuous and noxious stimuli.In other experiments, intracellular recordings were taken fromdorsal root ganglion neurons in vivo to identify changes thatmodel induction would produce in the primary sensory neurons,in order to lead to a better understanding of the peripheralmechanism and also the initiation of the pain in osteoarthritis.Surprisingly, it was found that large myelinated neuron, both highthreshold and low threshold neurones, underwent signicantchanges in our rat model of OA, and the changes observed differfrom those identied by others in models of inammatory pain.Conclusions: These studies have led to the identication ofunanticipated changes in both spinal cord and primary sensoryneurons. They thus raise new avenues to explore to understandthe pain of OA, as well as to develop novel therapeutic ap-proaches to treat the pain of OA. It can also be concluded that amultidisciplinary approach, such as that used here, is appropri-ate to assess novel therapeutics that might modify the originatingdisease, the clinical manifestation of pain, or both.Acknowledgements: This work has been generously supportedby the Canadian Arthritis Network, the Canadian Institutes ofHealth Research and McMaster University. The presenter grate-fully acknowledges the contributions of Neil Schwartz and WuQi.

    STRUCTURAL CORRELATES OF OA PAIN: MRI OF THEKNEEP.R. KornaatLeiden University Medical Center, Leiden, The NetherlandsAlthough radiographs remain the usual means of assessingosteoarthritic changes in the knee, the association betweenosteoarthritic ndings on radiographs and OA pain is poor. For-tunately, another imaging modality, magnetic resonance (MR)imaging, allows another perspective on the structural abnormali-ties associated with OA. MR imaging, with its excellent soft-tissuecontrast, is the best non-invasive technique currently availablefor the assessment of cartilage injury and other internal dear-rangements of the knee.A major hallmark of OA is cartilage loss. The exact causeof knee pain in patients with OA remains enigmatic becausehyaline cartilage does not contain pain bres and as such cannotbe the direct cause of pain in OA. Pain bres are present in otherstructures in the knee including the joint capsule, the periosteum,

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