PHARMACOLOGICAL CHARACTERIZATION OF THE NOCICEPTIN RECEPTOR MEDIATINGHYPERALGESIA IN THE MOUSE TAIL WITHDRAWAL ASSAY

1 The newly discovered neuropeptide nociceptin (NC) has recently been reported to be the endogenous ligand of the opioid-like orphan recepto r. Despite its structural similarity to opioids, when injected intrace rebroventricularly (i.c.v.) in the mouse, NC exerts a direct hyperalge sic effect and reverses opioid-induced analgesia. In the present inves tigation, these two effects of NC were evaluated under the same experi mental conditions; in addition, a pharmacological characterization of the receptor mediating these central effects of NC was attempted. 2 NC caused a dose dependent (0.1-10 nmol/mouse), naloxone-insensitive red uction of tail withdrawal latency with a maximal effect of about 50% o f the reaction time observed in saline injected mice. In the same rang e of doses, NC inhibited morphine (1 nmol/mouse) induced analgesia. 3 The effects of the natural peptide were mimicked by NCNH2 and NC(1-13) NH2 tall tested at 1 nmol/mouse) while 1 nmol NC(1-9)NH2 was found to be inactive either in reducing tail withdrawal latency or in preventin g morphine analgesia. 4 [Phe(1)psi/(CH2-NH)Gly(2)]NC(1 - 13)NH2 ([F/G] NC(1-13)NH2), which has been shown to antagonize NC effects in the mou se vas deferens, acted as an agonist, mimicking NC effects in both the experimental paradigms. In addition, when NC and [F/G]NC(1-13)NH2 wer e given together, their effects were additive. 5 These results demonst rate that both the direct hyperalgesic action and the anti-morphine ef fect of NC can be studied under the same experimental conditions in th e mouse tail withdrawal assay. Moreover, the pharmacological character ization of the NC functional site responsible for these actions compar ed with the peripherally active site, indicates the existence of impor tant differences between peripheral and central NC receptors.