Probable activation of the opioid receptor-nitric oxide-cyclic GMP-K+ channels pathway by codeine

There is evidence that local peripheral administration of morphine produces antinociception through the activation of the nitric oxide (NO)-cyclic GMP-K+ channels pathway. Therefore we evaluated the possible participation of this pathway in the antinociceptive action produced by codeine in the rat 5% formalin test. Local peripheral injection of codeine produced a dose-dependent antinociception during the first and second phases of the test. Local pretreatment of the paws with the NO synthase inhibitor NG-l-nitro-arginine methyl ester (l-NAME), the soluble guanylyl cyclase inhibitor methylene blue, the ATP-sensitive K+ channel inhibitors glibenclamide and tolbutamide, the non-selective voltage-gated K+ channel inhibitors 4-aminopyridine (4-AP) and tetraethylammonium (TEA) and the opioid receptor blocker naloxone prevented codeine-induced antinociception in both phases of the test. l-NAME, methylene blue, K+ channel blockers and naloxone by themselves did not modify formalin-induced nociceptive behavior. Our data suggest that codeine could activate the opioid receptor-NO-cyclic GMP-K+ channels pathway in order to produce its peripheral antinociceptive effect in the formalin test.