Orphan opioid receptor antisense probes block orphanin FQ-induced hyperphagia

We have exploited the availability of the "orphan" opioid receptor (referred to here as ORL1) in its "natural state" to investigate the effect of nociceptin (orphanin FQ), the endogenous agonist for the ORL1 receptor in the brain, vas deferens, and myenteric plexus of the small intestine. Nociceptin was a potent agonist in electrically stimulated preparations of vasa deferentia (rat and rabbit) and myenteric plexus (guinea-pig) (IC50 ranging from 18 to 31 nM) and susceptible to enzymic cleavage as addition of a cocktail of peptidase inhibitors to the organ bath produced a leftward shift in concentration-response curves (IC50 ranging from 2.1 to 4.9 nM). In radioligand binding experiments using brain membranes from rat, rabbit, and guinea-pig, [3H]nociceptin bound a single population of binding sites with high affinity (KD values ranging from 0.049 to 0.124 nM) and capacity (Bmax ranging from 143 to 254 fmol ·mg-1 protein). However, the response to nociceptin in functional studies and in radioligand binding inhibitory assays was resistant to antagonism/displacement by naloxone and a range of other opioid receptor antagonists, thus displaying a very different pharmacological profile from that of the "classical" opioids. Therefore, we conclude that the effect of nociceptin in these studies is not via an action at µ, delta , or kappa opioid receptors but rather at an orphan opioid receptor, ORL1.Key words: nociceptin, orphanin FQ, vas deferens, myenteric plexus, "orphan" opioid receptor.

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The relaxant effect of nociceptin on porcine coronary arterial ring segments

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y04-091 ◽

2004 ◽

Vol 82 (11) ◽

pp. 993-999 ◽

Cited By ~ 5

Author(s):

Pei-Han Xu ◽

Ming Chang ◽

Li-Xiang Cheng ◽

Qiang Cheng ◽

Xiang Yan ◽

...

Keyword(s):

Coronary Artery ◽

Opioid Receptor ◽

Coronary Arteries ◽

Isometric Tension ◽

Orphanin Fq ◽

Relaxant Effect ◽

Porcine Coronary Artery ◽

Prostaglandin F ◽

Key Words Nociceptin ◽

Β Receptor

Nociceptin (NC), alias orphanin FQ, has been identified as the endogenous ligand of the opioid receptor-like 1 receptor (ORL1). The purpose of this study was to assess the effect of nociceptin on porcine coronary arteries and to investigate the mechanism of its action, if any. Rings of coronary arteries from porcine hearts were suspended in baths containing Krebs solution, and isometric tension was measured. The response to nociceptin (10–12–10–5 mol/L) was investigated in porcine coronary arterial rings and also in such rings contracted with prostaglandin F2α (PGF2α). The effects of endothelium, nitroxide (NO), methylene blue, cyclic GMP (cGMP), naloxone, [Nphe1]NC(1–13)NH2, and propranolol on nociceptin-induced relaxation were also assessed. Our study showed nociceptin relaxed the porcine coronary arterial rings and inhibited the vasocontractivity to PGF2α. The relaxing response of nociceptin in coronary arteries was significantly reduced by removal of endothelium and by the presence of L-NNA, cGMP, and [Nphe1]NC(1–13)NH2, the selective nociceptin receptor antagonist, but not by naloxone, the nonselestive opioid receptor blocker or propranolol, which blocks the adrenergic β-receptor. Our results suggest that nociceptin induces relaxation of isolated coronary artery through NO, cGMP, and ORL1.Key words: nociceptin, porcine coronary artery, NO, ORL1.

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