Pharmacological characterization of the nociceptin receptor, ORL1 - Insight from the inward rectifier activation in the periaqueductal gray

A novel opioid receptor-like orphan receptor (ORL1) was cloned and identifi ed to be homologous to classical opioid receptors but insensitive to tradit ional opioids. A heptadecapeptide, termed orphanin FQ or nociceptin (OFQ/N) , was identified as its endogenous ligand. OFQ/N shares overlapping distrib ution sites in pain-processing areas and common cellular mechanisms with op ioids but exerts diverse effects on nociceptive responses. Of the two repor ted ORL1 antagonists, [Phe(1)psi(CH2-NH)-Gly(2)] nociceptin-(1-1 3)-NH2 (Ph e psi) and naloxone benzoylhydrazone (NBZ), antagonisms were validated in t he activation of inward rectifying K channels induced by OFQ/N, using the p atch clamp technique in ventrolateral periaqueductal gray slices. Results s howed that Phe psi acted as a partial agonist and NBZ was a weak nonselecti ve antagonist of ORL1. It is comparable with most but not all of the findin gs from other tissues. Comparing all the reports supports the above inferen ce for these two antagonists. The possible causes for the discrepancy were discussed. A brief review on the putative ORL1 antagonists, acetyl-RYYRIK-N H2, some sigma-ligands and the functional antagonist, nocistatin, is also i ncluded. It indicates that a potent and selective ORL1 antagonist is expect ing to elucidate the physiological role of OFQ/N, Copyright (C) 2000 Nation al Science Council. ROC and S. Karger AG, Basel.