Reversal by naloxone of the spinal antinociceptive actions of a systemically‐administered NSAID

Abstract

1 Possible interactions between non-steroidal anti-inflammatory drugs (NSAIDs) and endogenous opioids were examined in electrophysiological experiments in a-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 ,u-opioid agonist, fentanyl, was an effective depressant of reflexes under all conditions (ED50 6-14 ,ug kg-', 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-', 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-', 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 a2-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.

Differential effects of opioid-related ligands and NSAIDs in nonhuman primate models of acute and inflammatory pain

“…This suggests that ketorolac is ineffective in blocking hyperalgesia induced by agents that directly activate, rather than sensitize, the primary afferent nerve fibers (Brandt et al 2001; Negus et al 1995). It is reported that opioid receptor subtypes MOP, KOP and DOP as well as their endogenous agonists like β-endorphin, dynorphin and enkephalin are involved in the antihyperalgesic effects of some NSAIDs such as celecoxib and flunixin in the rodent carrageenan model (Correa et al 2010; Herrero and Headley 1996). In order to determine if antihyperalgesic effects of ketorolac are also mediated by opioid receptors, naltrexone was administered as a pretreatment.…”

The oral administration of retinoic acid enhances nociceptive withdrawal reflexes in rats with soft-tissue inflammation

“…Some studies, for example, have shown a clear relationship between retinoic acid and the generation of nitric oxide (NO) [9,12,28], prostaglandins [4,11] and the expression of cyclooxigenase 1 (COX-1) [23] and COX-2 [14,17]. All these mediators are involved in the generation or maintenance of sensitization and pain due to inflammation and are the targets for many painkillers studied in our lab among many others [7,10,26].…”

Interaction of the adenosine A1 receptor agonist N6-cyclopentyladenosine and κ-opioid receptors in rat spinal cord nociceptive reflexes

“…In these experiments, the effect of a single bolus of 16 μg/kg fentanyl was studied in the presence of 100 μg/kg naloxone injected 18 min before bolus administration (see also Herrero and Headley, 1996). The CPA vehicle was tested in control experiments (n = 3), using the same protocol as that described for the administration of CPA.…”