title: Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors.
abstract: It is generally believed that NMDA receptor antagonism accounts for most of the anesthetic and analgesic effects of ketamine, however, it interacts at multiple sites in the central nervous system, including NMDA and non-NMDA glutamate receptors, nicotinic and muscarinic cholinergic receptors, and adrenergic and opioid receptors. Interestingly, it was shown that at supraspinal sites, ketamine interacts with the μ-opioid system and causes supraspinal antinociception. In this study, we investigated the involvement of endogenous opioids in ketamine-induced central antinociception. The nociceptive threshold for thermal stimulation was measured in Swiss mice using the tail-flick test. The drugs were administered via the intracerebroventricular route. Our results demonstrated that the opioid receptor antagonist naloxone, the μ-opioid receptor antagonist clocinnamox and the δ-opioid receptor antagonist naltrindole, but not the κ-opioid receptor antagonist nor-binaltorphimine, antagonized ketamine-induced central antinociception in a dose-dependent manner. Additionally, the administration of the aminopeptidase inhibitor bestatin significantly enhanced low-dose ketamine-induced central antinociception. These data provide evidence for the involvement of endogenous opioids and μ- and δ-opioid receptors in ketamine-induced central antinociception. In contrast, κ-opioid receptors not appear to be involved in this effect.
authors.affiliation: Department of Pharmacology, Institute of Biological Sciences, UFMG, Av. Antônio Carlos, 6627, CEP 31.270.100, Belo Horizonte, Brazil.
authors.forename: Daniela da Fonseca
authors.initials: Dda F
authors.lastname: Pacheco
authors.affiliation: Department of Pharmacology, Institute of Biological Sciences, UFMG, Av. Antônio Carlos, 6627, CEP 31.270.100, Belo Horizonte, Brazil.
authors.forename: Thiago Roberto Lima
authors.initials: TR
authors.lastname: Romero
authors.affiliation: Department of Pharmacology, Institute of Biological Sciences, UFMG, Av. Antônio Carlos, 6627, CEP 31.270.100, Belo Horizonte, Brazil. Electronic address: dimitri@icb.ufmg.br.
authors.forename: Igor Dimitri Gama
authors.initials: ID
authors.lastname: Duarte
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002934:Cinnamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006358:Hot Temperature; D007649:Ketamine / Q000494:pharmacology*; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D009022:Morphine Derivatives / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D059226:Nociceptive Pain / Q000188:drug therapy / Q000378:metabolism; D018847:Opioid Peptides / Q000378:metabolism*; D058748:Pain Perception / Q000187:drug effects / Q000502:physiology; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000700:Analgesics; D002934:Cinnamates; D004791:Enzyme Inhibitors; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C076806:clocinnamox; D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone; D007649:Ketamine; D000626:Aminopeptidases; C055382:naltrindole; D007930:Leucine; C012211:ubenimex
keywords: Central antinociception; Endogenous opioid; Ketamine