Angiotensin-(1-7) through Mas receptor activation induces peripheral antinociception by interaction with adrenoreceptors

Abstract

Angiotensin-(1-7) [Ang-(1-7)] develops its functions interacting with Mas receptor. Mas receptor was recently identified in the DRG and its activation by Ang-(1-7) resulted in peripheral antinociception against PGE2 hyperalgesia in an opioid-independent pathway. Nevertheless, the mechanism by which Ang-(1-7) induce peripheral antinociception was not yet elucidated. Considering that endogenous noradrenaline could induce antinociceptive effects by activation of the adrenoceptors the aim of this study was verify if the Ang-(1-7) is able to induce peripheral antinociception by interacting with the endogenous noradrenergic system. Hyperalgesia was induced by intraplantar injection of prostaglandin E2 (2μg). Ang-(1-7) was administered locally into the right hindpaw alone and after either agents, α2-adrenoceptor antagonist, yohimbine (5, 10 and 20 μg/paw), α2C-adrenoceptor antagonist rauwolscine (10, 15 and 20 μg/paw), α1-adrenoceptor antagonist prazosin (0.5, 1 and 2 μg/paw), β-adrenoceptor antagonist propranolol (150, 300 and 600 ng/paw). Noradrenaline (NA) reuptake inhibitor reboxetine (30 μg/paw) was administered prior to Ang-(1-7) low dose (20 ng) and guanetidine 3 days prior to experiment (30 mg/kg/animal, once a day), depleting NA storage. Intraplantar Ang-(1-7) induced peripheral antinociception against hyperalgesia induced by PGE2. This effect was reversed, in dose dependent manner, by intraplantar injection of yohimbine, rauwolscine, prazosin and propranolol. Reboxetine intensified the antinociceptive effects of low-dose of Ang-(1-7) and guanethidine, which depletes peripheral sympathomimetic amines, reversed almost 70% the Ang-(1-7)-induced peripheral antinociception. Then, this study provides evidence that Ang-(1-7) induce peripheral antinociception stimulating an endogenous noradrenaline release that activates peripheral adrenoceptors inducing antinociception.

Keywords: Adrenergic system; Adrenoceptor; Angiotensin 1–7; Noradrenaline; Peripheral antinociception.