A cellular mechanism for the bidirectional pain-modulating actions of orphanin FQ/nociceptin

Orphanin FQ/nociceptin (OFQ/N) and its receptor share substantial structura l features and cellular actions with classic opioid peptides and receptors, but have distinct pharmacological profiles and behavioral effects. Current ly there is an active debate about whether OFQ/N produces hyperalgesia or a nalgesia. Using a well-defined brainstem pain-modulating circuit, we show t hat OFQ/N can cause either an apparent hyperalgesia by antagonizing mu opio id-induced analgesia or a net analgesic effect by reducing the hyperalgesia during opioid abstinence. It presumably produces these two opposite action s by inhibiting two distinct groups of neurons whose activation mediates th e two effects of opioid administration. OFQ/N antagonism of the hyperalgesi a may have significance for the treatment of opioid withdrawal and sensitiz ed pain.