Pharmacological evidence for the participation of NO–cyclic GMP–PKG–K+ channel pathway in the antiallodynic action of resveratrol

The possible participation of the nitric oxide (NO)–cyclic GMP–protein kinase G (PKG)–K+ channels pathway in the antiallodynic action of resveratrol and YC-1 in spinal nerve injured rats was assessed. Ligation of L5/L6 spinal nerves produced a clear-cut tactile allodynia in the rats. Intrathecal administration of resveratrol (100–600 μg) and 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (0.1–2.7 μg, YC-1, a soluble guanylyl cyclase activator) decreased tactile allodynia induced by ligation of L5/L6 spinal nerves. Intrathecal treatment with NG-l-nitro-arginine methyl ester (10–100 μg, l-NAME, a NO synthase inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (1–10 μg, ODQ, a soluble guanylyl cyclase inhibitor), KT-5823 (5–500 ng, a PKG inhibitor) and iberiotoxin (5–500 ng, a large-conductance Ca2+-activated K+ channel blocker), but not NG-d-nitro-arginine methyl ester (100 μg, d-NAME, an inactive isomer of l-NAME), glibenclamide (12.5–50 μg, ATP-sensitive K+ channel blocker) or vehicle, significantly diminished resveratrol (300 μg)- and YC-1 (2.7 μg)-induced spinal antiallodynia. These effects were independent of prostaglandin synthesis inhibition as indomethacin did not affect resveratrol-induced antiallodynia. Results suggest that resveratrol and YC-1 could activate the proteins of the NO–cyclic GMP–PKG spinal pathway or large-conductance Ca2+-activated, but not ATP-sensitive, K+ channels at the spinal cord in order to produce at least part of their antiallodynic effect in this model of neuropathy.