Opioidergic State-Control of Midbrain Nociception

The ventrolateral periaqueductal gray (vlPAG) facilitates pain and endogenous analgesia under different contexts via mu-opioid receptors (MORs) and enkephalin (Enk) signaling. However, our understanding of the endogenous opioid system and nociceptive cell-types in this region remains incomplete. Here, we used state-of-the-art mouse and viral genetic tools combined with behavior and in vivo optical recordings to further our understanding of vlPAG opioidergic neurocircuitry and elucidate endogenous opioid release dynamics under diverse pain conditions. We first genetically-captured and traced the nociceptive MOR population in vlPAG to reveal their distribution with a preponderance of activated cells in posterior vlPAG. We further found that these neurons projected broadly to other pain-associated nuclei throughout the brain: rostroventral medulla, ventral tegmental area, and thalamus, among others. Then, using fiber photometry calcium imaging, we found that vlPAG MOR neurons are acutely pain responsive and show decreased pain-related activity under conditions of either hindpaw inflammation or expected pain relief in a model of placebo analgesia. We hypothesized that these effects on vlPAG MOR neuron activity corresponded with changes in Enk release, which we detected with the Enk biosensor deltaLight. Crucially, we found that Enk release increases following onset of tonic, protracted pain states. In total, our data show that vlPAG MOR neurons are recruited by noxious stimulus exposure, but undergo endogenous opioid regulation when pain is prolonged or expectation of pain is altered. Our continuing and future work is aimed at addressing how vlPAG opioid circuitry interacts with other nociceptive brain areas across pain states. Funding: NIH F32DA055458 (Kimmey); Rita Allen Foundation Scholars Award in Pain (Corder).