title: The putative OP(4) antagonist, [Nphe(1)]nociceptin(1-13)NH(2), prevents the effects of nociceptin in neuropathic rats.
abstract: 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 OP(4). Elucidation of the biological role of N/OFQ has been hampered by the lack of compounds that selectively block the OP(4) receptor. Recently, a N/OFQ derivative, [Nphe(1)]N/OFQ(1-13)NH(2), has been found to possess OP(4) 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)NH(2) (20--120 nmoles, i.t.) was ineffective on its own. [Nphe(1)]N/OFQ(1-13)NH(2) (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 OP(4) receptor. This pseudopeptide is an interesting pharmacological tool to better clarify the role of N/OFQ in pathophysiology.
authors: Schering-Plough Research Institute, San Raffaele Science Park, via Olgettina, 58, 20132 Milan, Italy. laura.corradini@spcorp.com
authors: L
authors: L
authors: Corradini
authors: L
authors: L
authors: Briscini
authors: E
authors: E
authors: Ongini
authors: R
authors: R
authors: Bertorelli
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000588:Amines; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D003509:Cyclohexanecarboxylic Acids; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D000077206:Gabapentin; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009292:Narcotic Antagonists; D009294:Narcotics / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D018847:Opioid Peptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D017288:Pain Threshold / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism; D012584:Sciatic Nerve / Q000601:surgery; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D000085:Acetates; D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D000077206:Gabapentin; D009020:Morphine; D009292:Narcotic Antagonists; D009294:Narcotics; D018847:Opioid Peptides; D010446:Peptide Fragments; D011957:Receptors, Opioid; D005680:gamma-Aminobutyric Acid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C403776:nociceptin-(1-13)-NH2, NPhe(1)-; C000722285:Oprl1 protein, rat