Peripheral Antinociception Induced by Carvacrol in the Formalin Test Involves the Opioid Receptor-NO-cGMP-K+ Channels Pathway

Background/Objectives: Carvacrol is a naturally occurring phenolic monoterpene that is one of the major constituents of the essential oils of oregano (Origanum vulgare), thyme (Thymus vulgaris) and other herbs. Carvacrol has anti-inflammatory and antinociceptive effects. At the systemic level, carvacrol is able to activate and inhibit several second messengers and ion channels. However, there is no evidence on the peripheral antinociception of carvacrol and its probable mechanism of action. The aim of this study was to investigate whether the local antinociception of carvacrol involves the opioid receptor-nitric oxide (NO)-GMP-K+ channel pathway. Methods: Formalin (1%) was injected into the dorsal surface of the right hind paw of Wistar rats. Rats received a subcutaneous injection into the dorsal surface of the paw of vehicle or carvacrol (100-300 µg/paw). To determine whether the local antinociception induced by carvacrol was mediated by the opioid receptor-NO-cGMP-K+ channel pathway and a biguanide-dependent mechanism, the effect of pretreatment (10 min before formalin injection) with the corresponding vehicles, naltrexone, L-NAME, 1 H-(1,2,4)-oxadiazolo (4,2-a) quinoxalin-1-one (ODQ), K+ channel blockers, and metformin on the antinociceptive effects induced by local carvacrol (300 µg/paw) were evaluated. Results: Carvacrol produced antinociception during both phases of the formalin test. Naltrexone, L-NAME, ODQ, glibenclamide and glipizide (both ATP-sensitive K+ channel blockers), tetraethylammonium and 4-aminopyridine (both voltage-gated K+ channel blockers), apamin and charybdotoxin (both Ca2+-activated K+ channel blockers), and metformin reversed the carvacrol-induced peripheral antinociception. Conclusions: Local peripheral administration of carvacrol was able to produce significant antinociception and activate the opioid receptor-NO-cGMP-K+ channel pathway. In addition, carvacrol activated a metformin-dependent mechanism at the peripheral level.