title: Dextromethorphan and ketamine potentiate the antinociceptive effects of mu- but not delta- or kappa-opioid agonists in a mouse model of acute pain.
abstract: Animal and clinical studies have reported potentiation of opioid antinociception by NMDA receptor antagonists such as ketamine and dextromethorphan. The aim of this study was to compare these clinically available NMDA antagonists in combination with classical morphine, mu-selective fentanyl-like opioids, the delta-opioid agonist SNC80 and the kappa-opioid agonist U50,488H. Using a mouse hot-plate test, dose-response relationships were first determined for all compounds individually and then for opioids co-administered with fixed doses of ketamine or dextromethorphan. All compounds were administered intraperitoneally ED(50) values were calculated from the proportion of animals failing to exhibit any response within a fixed cut-off criterion of 30 s. To varying degrees, all compounds produced increases in response latencies over time. Dextromethorphan produced lower ED(50) values for morphine, fentanyl and sufentanil but exerted no effect on the potency of SNC80 or U50,488H. Similarly, ketamine potentiated the antinociceptive potency of morphine, fentanyl and sufentanil but not SNC80 or U50,488H. In summary, these results support the use of mu-opioid agonists in combination with NMDA antagonists, but suggest that there may be no advantage in combining dextromethorphan or ketamine with delta- or kappa-opioids in the management of acute pain.
authors.affiliation: CNS Discovery Research, Janssen Research Foundation, Turnhoutseweg 30, B-2340, Beerse, Belgium. abaker5@janbe.jnj.com
authors.forename: Alexis K
authors.initials: AK
authors.lastname: Baker
authors.forename: Vincent L H
authors.initials: VL
authors.lastname: Hoffmann
authors.forename: Theo F
authors.initials: TF
authors.lastname: Meert
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D001549:Benzamides / Q000494:pharmacology; D003915:Dextromethorphan / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005283:Fentanyl / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy* / Q000523:psychology; D010147:Pain Measurement / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D017409:Sufentanil / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D001549:Benzamides; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D007649:Ketamine; D003915:Dextromethorphan; D009020:Morphine; D017409:Sufentanil; D005283:Fentanyl