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

Pharmacological manipulations directed at the periaqueductal gray have demonstrated the importance of the mu-opioid receptor in modulating reflexive responses to nociception. We hypothesized that a supraspinal pathway centered on neurons in the periaqueductal gray containing the mu-opioid receptor could modulate nociceptive and itch behaviors.

We used anatomical, optogenetic, and chemogenetic approaches in male and female mice to manipulate mu-opioid receptor neurons in the periaqueductal gray. Behavioral assays including von Frey, Hargreaves, cold plantar, chloroquine-induced itch, hot plate, formalin-induced injury, capsaicin-induced injury, and open field tests were used. In separate experiments, we administered naloxone in a post-surgical model of latent sensitization.

Activation of mu-opioid receptor neurons in the periaqueductal gray increased jumping (least square (LS) mean difference of -3.30 seconds, 95% CI [-6.17, -0.44], p = 0.023, n = 7-8 mice per group), reduced itch responses (LS mean difference of 70 scratching bouts, 95% CI [35, 105], p < 0.001, n = 8 mice) and elicited modestly anti-nociceptive effects (LS mean difference of -0.7 grams on mechanical and -10.24 seconds on thermal testing, 95% CIs [-1.3, -0.2] and [-13.77, -6.70] and p = 0.005, p < 0.001, respectively, n = 8 mice). Lastly, we uncovered the role of the periaqueductal gray in suppressing hyperalgesia following a post-surgical state of latent sensitization (LS mean difference comparing saline and naloxone of -12 jumps, 95% CI [-17, -7], p < 0.001 for controls and -2 jumps, 95% CI [-7, 4], p = 0.706 following optogenetic stimulation, n = 7-9 mice per group).

Mu-opioid receptor neurons in the periaqueductal gray modulate distinct nocifensive behaviors: their activation reduced responses to mechanical and thermal testing, and attenuated scratching behaviors, but facilitated escape responses. Our findings emphasize the role of the periaqueductal gray in the behavioral expression of nociception using reflexive and noxious paradigms.