delta-Opioid receptor agonist SNC80 elicits peripheral antinociception via delta(1) and delta(2) receptors and activation of the l-arginine/nitric oxide/cyclic GMP pathway

In this study, we characterized the role of delta(1) and delta(2) opioids receptors, as well the involvement of the l-arginine/NO/cGMP pathway in the peripheral antinociception induced by delta-opioid receptor agonist (+)-4-(alphaR)-alpha-((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 E(2) (2 microg). Administration of SNC80 (20, 40 and 80 microg/paw) decreased the hyperalgesia induced by prostaglandin E(2) in a dose-dependent manner. The possibility that the higher dose of SNC80 (80 microg) 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 microg/paw, and 17-(Cyclopropylmethyl)-6,7-didehydro-3,14beta-dihydroxy-4,5alpha-epoxy-6,7-2',3'-benzob]furanomorphinan (naltriben), 2.5, 5 and 10 microg/paw, delta(1) and delta(2) opioid receptor antagonist respectively, elicited partial antagonism of the peripheral antinociceptive effect of the SNC80 (80 microg). The BNTX (10 microg/paw)-naltriben (5 microg/paw) combination completely antagonized the peripheral antinociception induced by SNC80 (80 microg). Further, blockers of the l-arginine/NO/cGMP pathway, N(G)-nitro-l-arginine (12, 18 and 24 microg/paw) and methylene blue (125, 250 and 500 microg/paw) were observed reverting the peripheral antinociceptive effect of SNC80. This study provides evidence that the peripheral antinociception induced by SNC80 occurs via delta(1) and delta(2) receptors and may result from l-arginine/NO/cGMP pathway activation.