The putative OP4 antagonist, [Nphe1]nociceptin(1-13)NH2, prevents the effects of nociceptin in neuropathic rats

Nociceptin or orphanin FQ (N/OFQ) is the natural ligand of the opioid receptor-like 1 receptor (ORL-1), which has been also classified as the fourth member of the opioid family of receptors and named OP4. Elucidation of the biological role of N/OFQ has been hampered by the lack of compounds that selectively block the OP4 receptor. Recently, a N/OFQ derivative, [Nphe(1)]N/OFQ(1-13)NH2, has been found to possess OP4 antagonistic properties both in vitro and in vivo models. We investigated its spinal effect in the chronic constriction injury of the sciatic nerve in the rat, a model relevant to neuropathic pain in humans. Intrathecal (i.t.) administration of N/OFQ (0.2-20 nmoles) dose-dependently reversed mechanical allodynic-like behavior, while [Nphe(1)]N/OFQ(1-13)NH2 (20-120 nmoles, i.t.) was ineffective on its own. [Nphe(1)]N/OFQ(1-13)NH2 (60-120 nmoles, i.t.) antagonized N/OFQ (about 80% of reduction) but did not modify the activity of morphine (20 nmoles, i.t.). These results further support, for the first time in a chronic model of pain, the specific antagonistic profile of [Nphe(1)]N/OFQ(1-13)NH(2)vs the OP4 receptor. This pseudopeptide is an interesting pharmacological tool to better clarify the role of N/OFQ in pathophysiology. (C) 2001 Published by Elsevier Science B.V.