Opioid receptor and NO/cGMP pathway as a mechanism of peripheral antinociceptive action of the cannabinoid receptor agonist anandamide.
OBJECTIVE
In this study, we investigated whether the opioid system and the nitric oxide pathway were involved in the peripheral antinociception induced by a cannabinoid receptor agonist anandamide.


METHODS
Hyperalgesia was induced by a subcutaneous injection of carrageenan (250 microg) into the plantar surface of the rat's hindpaw and measured by the paw pressure test 3h after injection. The weight in grams (g) required to elicit a nociceptive response, paw flexion, was determined as the nociceptive threshold.


RESULTS
Anandamide elicited a dose-dependent (50, 75, and 100 ng per paw) antinociceptive effect. The highest dose of anandamide did not produce antihyperalgesia in the contralateral paw, indicating a peripheral site of action. The CB(1) receptor antagonist AM251 (20, 40, 80 and 160mug per paw) antagonized peripheral antihyperalgesia induced by anandamide (100 ng), in a dose-dependent manner, suggesting CB(1) receptor activation. Anandamide-induced peripheral antihyperalgesia was reverted by blockers of the l-arginine/NO/cGMP pathway N(G)-nitro-l-arginine (NOARG; 24, 36 and 48 microg per paw) and 1H-[1,2,4] Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 25, 50 and 100 microg per paw), in a dose-dependent manner. Furthermore, opioid receptor antagonist naloxone (12.5, 25 and 50 microg per paw) antagonized the peripheral antihyperalgesia induced by anandamide.


CONCLUSIONS
This study provides evidence that the peripheral antinociceptive effect of the cannabinoid receptor agonist anandamide may result from l-arginine/NO/cGMP pathway activation and that the opioid system is also involved.
Reis
Gláucia Maria Lopes
GM
Department of Pharmacology, Institute of Biological Sciences, UFMG, 31270-100, Belo Horizonte, MG, CEP: 31.270-100, Brazil.
Pacheco
Daniela
D
Perez
Andréa Castro
AC
Klein
André
A
Ramos
Marina Abadia
MA
Duarte
Igor Dimitri Gama
ID
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000378:metabolism*; D015398:Signal Transduction
D000700:Analgesics; D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D011957:Receptors, Opioid; D009569:Nitric Oxide; D006152:Cyclic GMP; C078814:anandamide