Mu, Delta, and Kappa opioid receptor agonists induce peripheral antinociception by activation of endogenous noradrenergic system

Opioid receptor agonists induce noradrenaline release in the supraspinal, spinal, and peripheral sites. Endogenous noradrenaline release can induce an antinociceptive effect by activation of the a2 adrenoceptor. This interaction between the opioid and the adrenergic systems could be the alternative mechanism by which opioid receptor agonists mediate peripheral antinociception. Therefore, the aim of the present study was to verify whether peripheral antinociception induced by the mu, d, and ? opioid receptor agonists DAMGO, SNC80, and bremazocine, respectively, through the endogenous noradrenergic system. All drugs were administered locally into the right hind paw of male Wistar rats. The rat paw pressure test was used, with hyperalgesia induced by intraplantar injection of prostaglandin E2. DAMGO, SNC80, or bremazocine elicited local dose-dependent peripheral antinociception. This peripheral effect was antagonized by the nonselective a2 adrenoceptor antagonist yohimbine and by the selective a2C adrenoceptor antagonist rauwolscine but not by the selective antagonists for a2A, a2B, and a2D adrenoceptor subtypes (BRL 44 480, imiloxan, and RX 821002, respectively). The opioid-induced effect was antagonized by the nonselective a1 adrenoceptor antagonist prazosin and by the nonselective beta adrenoceptor antagonist propranolol. Guanethidine, a depletor of peripheral sympathomimetic amines, restored approximately 5060% of the opioid-induced peripheral antinociception. Furthermore, acute injection of the noradrenaline reuptake inhibitor reboxetine intensified the antinociceptive effects of low-dose DAMGO, SNC80, or bremazocine. This study provides evidence that DAMGO, SNC80, or bremazocine induces peripheral antinociception by noradrenaline release and interaction with adrenoceptors. (c) 2012 Wiley Periodicals, Inc.