Brainstem modulation of nociception by periaqueductal gray neurons expressing the mu-opioid receptor

Pharmacological manipulations directed at the periaqueductal gray (PAG) have revealed the importance of the mu-opioid receptor in the endogenous pain-modulatory system. Despite the clear role for opioidergic signaling within the PAG for the descending modulation of pain, the molecular and anatomical characterizations of neurons containing the mu-opioid receptor remain elusive. Using combinatorial anatomical, optogenetic, and chemogenetic approaches, we delineate a supraspinal pathway centered on PAGMOR neurons in the modulation of pain and itch behaviors. We found that chemogenetic manipulations of PAGMOR neurons in assays of nociception unveiled complex results; whereas activation of these neurons generally facilitated responses to noxious stimuli and jumping behaviors on the hotplate assay, opposing patterns were observed with reflexive responses to sensory testing. Activation of PAGMOR neurons also robustly inhibited itch. These dichotomous findings across distinct types of sensory testing emphasize the contextual behavioral expression of nociception using reflexive and noxious paradigms. Lastly, we uncovered the role for PBN projections in the PAG that modulate pain in an uninjured, post-surgical state of latent sensitization.