title: NOP receptor mediates anti-analgesia induced by agonist-antagonist opioids.
abstract: Clinical studies have shown that agonist-antagonist opioid analgesics that produce their analgesic effect via action on the kappa-opioid receptor, produce a delayed-onset anti-analgesia in men but not women, an effect blocked by co-administration of a low dose of naloxone. We now report the same time-dependent anti-analgesia and its underlying mechanism in an animal model. Using the Randall-Selitto paw-withdrawal assay in male rats, we found that nalbuphine, pentazocine, and butorphanol each produced analgesia during the first hour followed by anti-analgesia starting at ∼90min after administration in males but not females, closely mimicking its clinical effects. As observed in humans, co-administration of nalbuphine with naloxone in a dose ratio of 12.5:1 blocked anti-analgesia but not analgesia. Administration of the highly selective kappa-opioid receptor agonist U69593 produced analgesia without subsequent anti-analgesia, and confirmed by the failure of the selective kappa antagonist nor-binaltorphimine to block nalbuphine-induced anti-analgesia, indicating that anti-analgesia is not mediated by kappa-opioid receptors. We therefore tested the role of other receptors in nalbuphine anti-analgesia. Nociceptin/orphanin FQ (NOP) and sigma-1 and sigma-2 receptors were chosen on the basis of their known anti-analgesic effects and receptor binding studies. The selective NOP receptor antagonists, JTC801, and J-113397, but not the sigma receptor antagonist, BD 1047, antagonized nalbuphine anti-analgesia. Furthermore, the NOP receptor agonist NNC 63-0532 produced anti-analgesia with the same delay in onset observed with the three agonist-antagonists, but without producing preceding analgesia and this anti-analgesia was also blocked by naloxone. These results strongly support the suggestion that clinically used agonist-antagonists act at the NOP receptor to produce anti-analgesia.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of California, San Francisco, CA 94143-0440, United States.
authors.forename: R W
authors.initials: RW
authors.lastname: Gear
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of California, San Francisco, CA 94143-0440, United States.
authors.forename: O
authors.initials: O
authors.lastname: Bogen
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of California, San Francisco, CA 94143-0440, United States.
authors.forename: L F
authors.initials: LF
authors.lastname: Ferrari
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of California, San Francisco, CA 94143-0440, United States.
authors.forename: P G
authors.initials: PG
authors.lastname: Green
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of California, San Francisco, CA 94143-0440, United States; Department of Medicine, University of California at San Francisco, San Francisco, CA 94143-0120, United States. Electronic address: jon.levine@ucsf.edu.
authors.forename: J D
authors.initials: JD
authors.lastname: Levine
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D044482:Benzeneacetamides; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D008297:Male; D009266:Nalbuphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D018847:Opioid Peptides / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D011759:Pyrrolidines; D051381:Rats; D017207:Rats, Sprague-Dawley; D012733:Sex Differentiation; D000097629:Nociceptin
chemical_list: D000700:Analgesics; D044482:Benzeneacetamides; D009266:Nalbuphine; D009270:Naloxone; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011759:Pyrrolidines; D000097629:Nociceptin; C045444:U 69593
keywords: ANOVA; EDTA; FQ; HEPES; N-(2-hydroxyethyl)piperazine-N′-2-ethanesulfonic acid; NOP; analysis of variance; anti-analgesia; ethylenediaminetetraacetic acid; nalbuphine; nociceptin/orphanin; nociceptin/orphanin FQ receptor; nor-binaltorphimine; norBNI; receptor; κ-opioids