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 (ED(50) 6-14 mu g 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.