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 elic ited by noxious pinch and electrical stimuli. 2 The mu-opioid agonist, fentanyl, was an effective depressant of reflexes under all condition s (ED(50) 6-14 mu g kg(-1) i.v.). In rats without peripheral inflammat ion the NSAID, flunixin, a niflumic acid derivative, had only a small effect that was not dose-dependent. However, in animals with unilatera l inflammation, flunixin reduced spinal reflexes evoked both by noxiou s pinch stimuli (that activate peripheral nociceptors; ID50 4 mg kg(-1 ), i.v.) and by electrical stimuli (that bypass nociceptor endings; ID 50 6.5-11 mg kg(-1), i.v.), indicating that it has a central site of a ction at doses comparable to those used clinically. 3 The opioid antag onist, naloxone (1 mg kg(-1), i.v.), reversed all actions of fentanyl. It did not reverse the small effects that flunixin had in rats withou t 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 W e conclude that under conditions of peripheral inflammation and the re sultant central changes, the NSAID, flunixin, has antinociceptive acti ons that are mediated by endogenous opioids acting within the spinal c ord.