Possible participation of the nitric oxide-cyclic GMP-protein kinase G-K + channels pathway in the peripheral antinociception of melatonin

Abstract

The possible participation of the nitric oxide (NO)-cyclic GMP-protein kinase G (PKG)-K + channel pathway on melatonin-induced local antinociception was assessed during the second phase of the formalin test. The local peripheral ipsilateral, but not contralateral, administration of melatonin (150—600 μg/paw) produced a dose-related antinociception during both phases of the formalin test in rats. Moreover, local pretreatment with N G- l-nitro-arginine methyl ester ( l-NAME, NO synthesis inhibitor, 10–100 μg/paw), 1 H-(1,2,4)-oxadiazolo(4,2- a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor, 5–50 μg/paw), (9 S, 10 R, 12 R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1 H-diindolo [1,2,3- fg:3′,2′,1′- kl]pyrrolo [3,4- i][1,6] benzodiazocine-10-carboxylic acid methyl ester (KT-5823, specific PKG inhibitor, 50–500 ng/paw), glibenclamide (ATP-sensitive K + channel blocker, 5–50 μg/paw), apamin (small-conductance Ca 2+-activated K + channel blocker, 0.1–1 μg/paw) or charybdotoxin (large- and intermediate-conductance Ca 2+-activated K + channel blocker, 0.03–0.3 μg/paw), but not N G- d-nitro-arginine methyl ester ( d-NAME, inactive isomer of l-NAME, 100 μg/paw) or vehicle, significantly prevented melatonin (300 μg/paw)-induced antinociception. Data suggest that melatonin-induced local peripheral antinociception during the second phase of the test could be due to activation of the NO-cyclic GMP-PKG-ATP-sensitive and Ca 2+-activated K + channels pathway.