Blockade of the antinociceptive activity of centrally administered ketorolac by nor-binaltorphimine.
Antinociceptive activity of intracerebroventricularly administered ketorolac tromethamine was evaluated in mice by measuring inhibition of abdominal stretching induced by p-phenylquinone. Ketorolac tromethamine produced dose-dependent antinociception with an ED50 of 7.34 micrograms/mouse (4.97-10.82) and a maximal effect at 30 micrograms. Selective antagonists of opioid receptors were used to determine ketorolac's mechanism of action. The ketorolac tromethamine-induced antinociception was not blocked by the mu- and delta-opioid receptor antagonists, naloxone and ICI-174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu), respectively; however, the kappa-opioid receptor antagonist nor-binaltorphimine dihydrochloride significantly blocked this effect. These findings suggest that activation of kappa-opioid receptors appears to play a role in the mechanism of the antinociceptive effect of ketorolac tromethamine. Ketorolac tromethamine may induce the release of endogenous kappa-opioids to produce central nervous system antinociception.
Tripathi
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Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613, USA.
Welch
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D000698:Analgesia; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004743:Enkephalin, Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D007276:Injections, Intraventricular; D020911:Ketorolac Tromethamine; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D014046:Tolmetin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity; D014325:Tromethamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity
D018712:Analgesics, Non-Narcotic; D016227:Benzoquinones; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D014325:Tromethamine; C029322:phenylbenzoquinone; D009270:Naloxone; C051844:norbinaltorphimine; D020911:Ketorolac Tromethamine; D004743:Enkephalin, Leucine; D009271:Naltrexone; C040643:N,N-diallyl-tyrosyl-alpha-aminoisobutyric acid-phenylalanyl-leucine; D014046:Tolmetin