Circuitry and Molecular Mechanisms for Descending Pain Facilitation

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.

Grant Number: 5R01NS129834-03
NIH Institute/Center: NIH
Principal Investigator: Xiaoke Chen