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

• Published in: Journal of neuroscience research 2012-08, Vol.90 (8), p.1654-1661
• Main Authors: Romero, Thiago R.L., Guzzo, Luciana S., Duarte, Igor D.G.
• Format: Article
• Language: English
• Subjects: adrenoceptor; Analgesics, Opioid - pharmacology; Animals; endogenous noradrenaline; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Hyperalgesia - metabolism; Male; Norepinephrine - secretion; opioid agonists; opioid receptor; Pain Threshold - drug effects; peripheral antinociception; Rats; Rats, Wistar; Receptors, Opioid - agonists
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.23050

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 α2 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 μ, δ, and κ 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 α2 adrenoceptor antagonist yohimbine and by the selective α2C adrenoceptor antagonist rauwolscine but not by the selective antagonists for α2A, α2B, and α2D adrenoceptor subtypes (BRL 44 480, imiloxan, and RX 821002, respectively). The opioid‐induced effect was antagonized by the nonselective α1 adrenoceptor antagonist prazosin and by the nonselective β adrenoceptor antagonist propranolol. Guanethidine, a depletor of peripheral sympathomimetic amines, restored approximately 50–60% 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. © 2012 Wiley Periodicals, Inc.