Reversal by naloxone of the spinal antinociceptive actions of a systemically-administered NSAID.
1. Possible interactions between non-steroidal anti-inflammatory drugs (NSAIDs) and endogenous opioids were examined in electrophysiological experiments in alpha-chloralose anaesthetized spinalized rats without or with carrageenan-induced acute inflammation of one hindpaw. Spinal reflex responses, monitored as single motor unit discharges, were elicited by noxious pinch and electrical stimuli. 2. The mu-opioid agonist, fentanyl, was an effective depressant of reflexes under all conditions (ED50 6-14 micrograms kg-1, i.v.). In rats without peripheral inflammation the NSAID, flunixin, a niflumic acid derivative, had only a small effect that was not dose-dependent. However, in animals with unilateral inflammation, flunixin reduced spinal reflexes evoked both by noxious pinch stimuli (that activate peripheral nociceptors; ID50 4 mg kg-1, i.v.) and by electrical stimuli (that bypass nociceptor endings; ID50 6.5- 11 mg kg-1, i.v.), indicating that it has a central site of action at doses comparable to those used clinically. 3. The opioid antagonist, naloxone (1 mg kg-1, i.v.), reversed all actions of fentanyl. It did not reverse the small effects that flunixin had in rats without inflammation, showing that the NSAID is not a direct opioid agonist. In rats with carrageenan-induced inflammation of the hindpaw, however, naloxone fully reversed or prevented the antinociception by flunixin, but not that by the alpha 2-adrenoceptor agonist, medetomidine. 4. We conclude that under conditions of peripheral inflammation and the resultant central changes, the NSAID, flunixin, has antinociceptive actions that are mediated by endogenous opioids acting within the spinal cord.
Herrero
J F
JF
Department of Physiology, University of Bristol, School of Medical Sciences.
Headley
P M
PM
D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002351:Carrageenan; D003002:Clonixin / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005079:Excipients; D005283:Fentanyl / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced; D008297:Male; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005079:Excipients; D009292:Narcotic Antagonists; C014557:flunixin; D009270:Naloxone; D002351:Carrageenan; D005283:Fentanyl; D003002:Clonixin