ORL-1: An awkward child of the opioid receptor family

The cloning of the delta-opioid receptor allowed for the rapid cloning of the two other classically defined opioid receptors, the mu- and kappa-opioid receptors. However, several groups cloned a fourth receptor (ORL-1, for opioid receptor-like) that had high homology to the opioid receptors but did not bind any known endogenous opioid peptides (i.e., endorphins) or exogenous opiates. Recently, two independent groups isolated a 17-amino-acid peptide that is an endogenous ligand for ORL-1; one group named it orphanin FQ (OFQ), the other named it nociceptin (N). It was reported that intracerebroventricular administration of this heptadecapeptide (OFQ/N) in mice induced an increased responsiveness to painful stimuli, an effect in striking contrast to the analgesia that is a hallmark of classical opiate drugs. Further research has revealed that OFQ/N has complex effects on pain perception: OFQ/N has been touted as having analgesic, hyperalgesic, and antiopioid properties. In addition to discussing these disparate findings, this review highlights the structural and pharmacological parallels between ORL-1 and opioid receptors as well as their respective endogenous ligands.