Pharmacological characterization of the nociceptin receptor mediating hyperphagia: identification of a selective antagonist.

摘要

RATIONALE: Central injections of nociceptin (NC) stimulate feeding in rats. OBJECTIVE: The present study evaluated the effect of N-terminal partial sequences or analogues of NC on food intake in male Wistar rats, to characterize pharmacologically the NC receptor mediating the hyperphagic effect. METHODS: NC and related peptides were injected into the lateral (LV) or third (3V) cerebroventricle in freely feeding rats. RESULTS: In the LV, NC stimulated feeding. The N-terminal fragment NC(1-13)NH2 proved to be the least active sequence with hyperphagic activity; NC(1-12)NH2 and NC(1-9)NH2 were inactive. [Phe(1)psi(CH2-NH)Gly(2)]NC(1-13)NH2 ([F/G)]NC(1-13)NH2), an analogue of NC(1-13)NH2, markedly stimulated feeding and, coadministered in the LV with NC, never reduced the hyperphagic effect of the natural sequence. These findings suggest that [F/G)]NC(1-13)NH2, which has been reported to act as a NC receptor antagonist in peripheral tissues, behaves as a full agonist at the central NC receptors controlling feeding. The hyperphagic potencies of NC and [F/G)]NC(1-13)NH2 were much higher following injection into the 3V than in the LV. Another analogue of NC(1-13)NH2, namely [Nphe(1)]NC(1-13)NH2, injected into the 3V did not stimulate feeding, but reduced the effect of NC. [Nphe(1)]NC(1-13)NH2 at a dose of 16.8 nmol/rat significantly reduced, and at 168 nmol/rat almost completely abolished the effect of NC (1.68 nmol/rat). The latter dose of [Nphe(1)]NC(1-13)NH2 significantly reduced also feeding induced by food deprivation, but did not modify the hyperphagic effect of neuropeptide Y (0.3 nmol/rat). CONCLUSIONS: The present results confirm the orexigenic effect of NC in freely feeding rats and indicate that [Nphe(1)]NC(1-13)NH2 may represent a selective NC receptor antagonist to study the physiological and pathophysiological role of NC in feeding behaviour.