Central sensitization in osteoarthritis pain: Validation of rodent models, development of biomarkers for diagnosis and anti-inflammatory inhibitors for treatment.

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Osteoarthritis (OA) is the most common form of arthritis and a major cause of pain and disability in older adults. We hypothesized that innate immune system activation, best documented in response to pathogens, likely plays a role in the induction of inflammatory mediators and the specific cellular infiltrates seen in OA. We previously linked immune system activation to the processes of sensitization, thought to be the basis for arthritic pain that appears spontaneously (that is, at rest), and hyperalgesia (increased pain responses to noxious stimulation) and allodynia (pain in response to normally non-painful stimulation). We demonstrated this in both experimental rat and dog, as well as natural cat and dog, OA models. Sensitization also facilitates the efferent neuronal processes through which the nervous system influences the inflammatory/immune process. This could contribute to the frequently observed disparity between clinical pain severity and the extent of joint changes in subjects with OA. Such observations have prompted work to investigate the mechanisms of central pain perception in OA. By studying chronic pain syndromes in different species, we have validated a method of central sensitization assessment that includes specific neuroproteome quantification, neuromechanical testing, neurophysiological sensitization testing (mechanical temporal summation) and functional neuroimaging. We will apply these to the determination of the experimental rat OA model best suited to studying sensitization, before confirming the role of inflammatory/immune signalling pathways using genetically modified mouse models. Finally, to study the central role of pro-inflammatory cytokines in OA structure and pain pathogenesis, we will block interleukin-1 receptor binding using various pharmacological approaches. Our hypothesis is that the inhibition produced by an original negative allosteric modulator will have the greatest effects on joint alterations and neuronal sensitization, along with the fewest side effects. This will open the field for an innovative anti-inflammatory pharmacological approach to early OA.