[Tyr1]-nociceptin has naloxone-insensitive vasodilator activity in the hindquarters vascular bed of the rat.
The heptadecapeptide nociceptin, also known as Orphanin FQ, is a newly-discovered endogenous ligand for the opioid-like G-protein-coupled receptor ORL1. In the present study, in order to investigate the structure-activity relationship for nociceptin, responses to nociceptin, [Tyr1]-nociceptin, nociceptin-(2-17), nociceptin-(1-11), and nociceptin-(1-7) were compared in the hindquarters vascular bed of the rat. Injections of nociceptin (1-30 nmol), [Tyr1]-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, [Tyr1]-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 nociceptin-(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 [Tyr1]-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 [Tyr1]-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.
Champion
H C
HC
Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Kadowitz
P J
PJ
D000818:Animals; D005260:Female; D008297:Male; D009270:Naloxone / Q000494:pharmacology*; D018847:Opioid Peptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists; D014664:Vasodilation / Q000187:drug effects*; D000097629:Nociceptin
D009270:Naloxone; D018847:Opioid Peptides; D010446:Peptide Fragments; D011957:Receptors, Opioid; D000097629:Nociceptin