Pharmacological Characterization of the Nociceptin Receptor, ORL1

Abstract

A novel opioid receptor-like orphan receptor (ORL1) was cloned and identified to be homologous to classical opioid receptors but insensitive to traditional opioids. A heptadecapeptide, termed orphanin FQ or nociceptin (OFQ/N), was identified as its endogenous ligand. OFQ/N shares overlapping distribution sites in pain-processing areas and common cellular mechanisms with opioids but exerts diverse effects on nociceptive responses. Of the two reported ORL1 antagonists, [Phe¹ψ(CH₂-NH)- Gly²] nociceptin-(1–13)-NH₂ (Pheψ) and naloxone benzoylhydrazone (NBZ), antagonisms were validated in the activation of inward rectifying K channels induced by OFQ/N, using the patch clamp technique in ventrolateral periaqueductal gray slices. Results showed that Pheψ acted as a partial agonist and NBZ was a weak nonselective antagonist of ORL1. It is comparable with most but not all of the findings from other tissues. Comparing all the reports supports the above inference for these two antagonists. The possible causes for the discrepancy were discussed. A brief review on the putative ORL1 antagonists, acetyl-RYYRIK-NH2, some σ-ligands and the functional antagonist, nocistatin, is also included. It indicates that a potent and selective ORL1 antagonist is expecting to elucidate the physiological role of OFQ/N.

Pharmacological Characterization of Nociceptin/Orphanin FQ Receptors, a Novel Opioid Receptor Family, in the Midbrain Periaqueductal Gray

“…Naloxone benzoylhydrazone (NalBzOH) had been reported to be an antagonist and agonist, respectively, at μ‐ and κ‐opioid receptors14 before NOP receptors were discovered. It was later found to act as a NOP antagonist in studies in vitro and in vivo 13. In vlPAG neurons, we have found that NalBzOH is a competitive antagonist of NOP receptors that mediate GIRK channel activation with a pA2 value of 5.67 9.…”

“…In vlPAG neurons, we found that it activated GIRK channels, as did N/OFQ, although it antagonized the effect of N/OFQ, that is, acting as a partial agonist at the native NOP receptors of the midbrain PAG 12. Thereafter, several reports also proved that it is a partial agonist of NOP receptors in central and peripheral nervous systems and has intrinsic activity at the NOP receptors involved in nociception as well as cardiovascular and renal functions 6,13…”

“…However, it also acts as a noncompetitive and more potent antagonist of μ‐opioid receptors in the same preparation 9. NalBzOH has been found to have intrinsic activity at NOP receptors in some studies13,15 but not in other studies,16 including ours 9…”

Biomedical Vignette

“…[Phe 1 (CH 2 -NH)Gly 2 ] nociceptin-(1-13)-NH 2 (Phe ), naloxone benzoylhydrazone (NBZ), acetyl-RYYR1K-NH 2 and nocistatin, have been reported [7], their mode of action remains elusive. Chiou [3] reported that none of the putative ORL1 antagonists as listed above could be considered as specific and potent antagonist for the ORL1 receptors as measured from the inward rectifier activation in the periaqueductal gray neurons. These observations point to the urgent need for the development of a new generation of ORL1 antagonists.…”