Understanding and treating osteoarthritic pain in pet animals: An approach based on neurogenomics and neuropeptidomics manipulation

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Pain is a complex, subjective phenomenon that causes feelings of physical and emotional discomfort; It is commonly underdiagnosed and under treated in pet animals. Within the last 50 years, few effective treatments for chronic pain have emerged, largely because the mechanisms of these disorders are incompletely understood. This lack of insight is astounding when we consider that chronic osteoarthritis (OA) pain affects approximately 20% of the adult feline and canine population in Western societies. When we are posed with a clinical pain problem, we follow a set of time-tested techniques. This involves understanding the anatomic substrate, which, in pain medicine is the `pain generator'. We further probe into the etio-pathophysiology (or cause and process) underlying the problem: neural transmitters/ modulators (ligands and receptors) and other chemicals involved in the generation, propagation and modulation of pain. This is the current state of clinical pain in veterinary medicine. Advances in neuroscience now make it possible to postulate the various neural networks involved in pain development and maintenance. Without an understanding of these networks, we are unable to address the issue of pain fully. Comprehending pain at a molecular level increases the effectiveness of already established network level knowledge. Genomics and proteomics are relatively new and rapidly expanding research areas in the 21st century, and contribute to conventional research tools. We have developed and validated a pain behavior assessment battery focusing on biomechanical and somato-sensory sensitivity alterations in OA rats. This allows to characterize every level of the neurophysiological OA pain process, namely peripheral sensitivity, spinal sensitization, and descending (superior) inhibitory control. In addition, we have established spinal neuropeptidome changes associated with the OA disease. Based on our recent discoveries, our aim is to pursue investigations on the neuro-peptidomics/ genomics crosstalk in the OA pain process, to determine new molecular targets of OA pain modulation in pet animals. Our specific objectives will be i) to use a rat surgical OA pain model to detect the cellular source and the function of the three most relevant neuropeptides established in our previous OA studies; ii) to generate specific gene silencing of selected neuropeptides, i.e., substance P, somatostatin and transthyretin, and characterize their consequences on pain phenotype in our established chronic OA pain model in rats; and iii) to extend the most interesting finding in the rat model to naturally-occurring OA in cats. We have a unique access to colony of pet animals naturally-affected by OA. Therefore, the pharmacogenetic silencing (or modulation) of peripheral nociceptors, central transmitters, determined on the basis of neuro-proteomic/ genomic findings, and demonstrated as efficient in the rat model, will be tested on OA cats.