TYR 1]-NOCICEPTIN HAS NALOXONE-INSENSITIVE VASODILATOR ACTIVITY IN THE HINDQUARTERS VASCULAR BED OF THE RAT

Abstract

The heptadecapeptide nociceptin, also known as Orphanin FQ, is a newly-discovered endogenous ligand for the opioid-like G-protein-coupled receptor ORL 1. In the present study, in order to investigate the structure-activity relationship for nociceptin, responses to nociceptin, [Tyr 1]-nociceptin, nociceptin- [2–17], nociceptin- [1–11], and nociceptin- [1–7] of nociceptin (1–30 nmol), [Tyr 1]-nociceptin (1–30 nmol), and met-enkephalin (10–300 nmol) induced dose-related decreases in hindquarters perfusion pressure, whereas injections of similar volumes of the saline vehicle had no effect. In terms of relative vasodilator activity, [Tyr 1]-nociceptin was similar to nociceptin, and these peptides were approximately 10-fold more potent than met-enkephalin in decreasing hindquarters perfusion pressure. In contrast, nociceptin- [2–17], nociceptin- [1–11], and niciceptin- [1–7] had no significant effect on hindquarters perfusion pressure when injected into the perfusion circuit in doses up to 100 nmol. The decreases in hindquarters perfusion pressure in response to [Tyr 1]-nociceptin and nociceptin were not altered by the opioid receptor antagonist naloxone at a time when responses to met-enkephalin were reduced significantly. The results of the present study show that [Tyr 1]-nociceptin and nociceptin have similar vasodilator activity in the hindquarters vascular bed and that responses to this novel nociceptin analog are not mediated by the activation of a naloxone-sensitive opioid receptor and are not dependent on the presence of the amino acid Phe at the N-terminus of the nociceptin sequence. Moreover, the results of the present study show that nociceptin- [2–17], nociceptin [1–11], and nociceptin- [1–7] have no activity in the hindquarters vascular bed of the rat when injected in doses up to 100 nmol. © 1997 Elsevier Science Inc.