title: 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.
abstract: 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'-benzo[b]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.
authors.affiliation: Department of Pharmacology, Institute of Biological Sciences, UFMG, Av. Antônio Carlos, 6627, 31.270.100, Belo Horizonte, Brazil.
authors.forename: Daniela F
authors.initials: DF
authors.lastname: Pacheco
authors.forename: Gláucia M L
authors.initials: GM
authors.lastname: Reis
authors.forename: Janetti N
authors.initials: JN
authors.lastname: Francischi
authors.forename: Maria S A
authors.initials: MS
authors.lastname: Castro
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Perez
authors.forename: Igor D G
authors.initials: ID
authors.lastname: Duarte
mesh_terms: D000700:Analgesics; D000818:Animals; D001120:Arginine / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000494:pharmacology; D006152:Cyclic GMP / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000187:drug effects*
chemical_list: D000700:Analgesics; D001549:Benzamides; D001597:Benzylidene Compounds; D004791:Enzyme Inhibitors; D010879:Piperazines; D017465:Receptors, Opioid, delta; C068868:naltrindole benzofuran; C077358:7-benzylidenenaltrexone; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D019335:Nitroarginine; D009569:Nitric Oxide; D009271:Naltrexone; D001120:Arginine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D015232:Dinoprostone