Peripheral antinociception induced by δ-opioid receptors activation, but not μ- or κ-, is mediated by Ca2 +-activated Cl− channels

Abstract

Studies have demonstrated that the L-arginine/NO/cGMP pathway and the potassium and calcium channels are involved in the mechanisms underlying opioid receptor activation. As additional pathways may participate in the observed antinociceptive effects following opioid exposure, the aim of our study was to determine whether Ca2+-activated Cl− channels (CaCCs) are involved in peripheral antinociception induced by μ-, δ- and κ-opioid receptor activation. Hyperalgesia was induced by intraplantar injection of prostaglandin E2 (PGE2, 2μg). Nociceptive thresholds to pressure (grams) were measured using an algesimetric apparatus 3h following injection. The μ-opioid receptor agonist morphine (200μg), δ-opioid receptor agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80, 80μg), κ-opioid receptor agonist bremazocine (50μg), CaCCs blocker niflumic acid (8–64μg), CaCCs blocker 5-Nitro-2-(3-phenylpropylamino) benzoic acid (NPPB, 32–128μg), nitric oxide donor sodium nitroprusside (SNP, 500μg) and cGMP exogenous analogs dibutyryl cGMP (db-cGMP, 100μg) were also administered into the paw. The CaCCs blocker niflumic acid and NPPB partially reversed the peripheral antinociception induced by exposure to the SNC80 in a dose-dependent manner. In contrast, niflumic acid did not modify the antinociceptive effect observed following exposure to morphine or bremazocine. Additionally, the peripheral antinociception induced by the NO donor SNP or by db-cGMP was not inhibited by niflumic acid. These results provide evidence for the involvement of CaCCs in the peripheral antinociception induced by SNC80. CaCCs activation does not appear to be involved when μ- and κ-opioid receptors are activated. In addition, we did not observe a link between CaCCs and the L-arginine/NO/GMPc pathway.