Circuitry and Molecular Mechanisms for Descending Pain Facilitation

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Abstract Chronic pain is a pervasive global health issue affecting about 20% of individuals worldwide, but available treatments for chronic pain are still inadequate. Opiates have been used for centuries as potent analgesics, but issues with tolerance, abuse, and overdose have contributed to current opioid crisis in the US. On the other hand, it is well documented that the level of perceived pain can be strongly influenced by cognitive and mood states, revealing the existence of powerful endogenous top-down modulation of pain. However, the therapeutic potential of targeting descending pain modulation pathway in treating chronic pain has not been extensively explored, in a large part because of our poor understanding of the circuitry and molecular mechanisms underlying how these descending pathways engage in chronic pain. In our preliminary studies, we developed novel genetic and viral tools, and gained robust access to the -opioid receptor expressing spinal cord projecting neurons in the rostroventral medulla (OPRM+ RVMSC neurons). We demonstrated that the OPRM+ RVMSC neurons has limited contribution to normal nociception but is required for both initiation and maintenance of nerve injury induced chronic mechanical pain. We therefore established these neurons as a potent cellular target for treating chronic pain. In this proposal, we will further examine the circuitry (Aim1) and molecular (Aim2) mechanisms that engage the OPRM+ RVMSC neurons in chronic pain. These proposed studies will not only advance our understanding of how the OPRM+ RVMSC neurons is recruited in chronic pain, but also inspire the development of novel non-opioid treatment for chronic pain.