δ-Opioid receptor agonist SNC80 elicits peripheral antinociception via δ1 and δ2 receptors and activation of the l-arginine/nitric oxide/cyclic GMP pathway

In this study, we characterized the role of δ1 and δ2 opioids receptors, as well the involvement of the l-arginine/NO/cGMP pathway in the peripheral antinociception induced by δ-opioid receptor agonist (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). The paw pressure test was utilized, in which pain sensitivity is increased by intraplantar injection of prostaglandin E2 (2 μg). Administration of SNC80 (20, 40 and 80 μg/paw) decreased the hyperalgesia induced by prostaglandin E2 in a dose-dependent manner. The possibility that the higher dose of SNC80 (80 μg) has a central or systemic effect was excluded, since administration of the drug into the contralateral paw did not elicit antinociception in the right paw. 7-Benzylidenenaltrexone (BNTX), 5, 10 and 20 μg/paw, and 17-(Cyclopropylmethyl)-6,7-didehydro-3,14β-dihydroxy-4,5α-epoxy-6,7-2′,3′-benzo[b]furanomorphinan (naltriben), 2.5, 5 and 10 μg/paw, δ1 and δ2 opioid receptor antagonist respectively, elicited partial antagonism of the peripheral antinociceptive effect of the SNC80 (80 μg). The BNTX (10 μg/paw)-naltriben (5 μg/paw) combination completely antagonized the peripheral antinociception induced by SNC80 (80 μg). Further, blockers of the l-arginine/NO/cGMP pathway, NG-nitro-l-arginine (12, 18 and 24 μg/paw) and methylene blue (125, 250 and 500 μg/paw) were observed reverting the peripheral antinociceptive effect of SNC80. This study provides evidence that the peripheral antinociception induced by SNC80 occurs via δ1 and δ2 receptors and may result from l-arginine/NO/cGMP pathway activation.