The periaqueductal grey (PAG), a small nucleus in the brain stem, has a crucial role in central analgesia; direct application of opioids into the PAG inhibits GABA neurons through both GIRK-independent (presynaptic) and GIRK-dependent (postsynaptic) mechanisms, which is sufficient to induce analgesia140,141. The disinhibition of principal neurons of PAG that project to nuclei of the caudal brain stem and modulate ascending pain pathways likely plays a significant role in the analgesic effects of opioids.
