Study of the involvement of K+ channels in the peripheral antinociception of the K-opioid receptor agonist bremazocine

The involvement of the nitric oxide (NO)/cyclic GMP pathway in the molecular mechanisms of antinociceptive drugs like morphine has been previously shown by our group. Additionally, it is known that the desensitisation of nociceptors by K+ channel opening should be the final target for several analgesic drugs including nitric oxide donors and exogenous mu-opioid receptor agonists. In our previous study, we demonstrated that bremazocine, a kappa-opioid receptor agonist, induces peripheral antinociception by activating nitric oxide/cyclic GMP pathway. In the current study, we assessed whether bremazocine is capable to activate K+ channels eliciting antinociception. Bremazocine (20, 40 and 50 mug) dose-dependently reversed the hyperalgesia induced in the rat paw by local injection of carrageenan (250 mug) or prostaglandin E-2 (2 mug), measured by the paw pressure test. Using the selective kappa-opioid receptor antagonist norbinaltorphimine (Nor-BNI, 200 mug/paw), it was confirmed that bremazocine (50 mug/paw) acts specifically on the kappa-opioid receptors present at peripheral sites. Prior treatment with the ATP-sensitive K+ channel blockers glibenclamide (40, 80 and 160 mug) and tolbutamide (40, 80 and 160 mug) did not antagonise the antinociceptive effect of bremazocine (50 mug). The same results were obtained when we used prostaglandin E-2 (2 mug) as the hyperalgesic stimulus. The supposed participation of other types of K+ channels was tested using the Ca2+-activated K+ channel blockers dequalinium (12.5, 25 and 50 mug) and charybdotoxin (0.5, 1 and 2 mug) and different types of the non-selective K+ channel blockers tetraethylammonium (25, 50 and 100 mug) and 4-aminopyridine (10, 25 and 50 mug). None of the K+ channel blockers reversed the antinociceptive effect of bremazocine. On the basis of these results, we suggest that K+ channels are not involved in the peripheral antinociceptive effect of bremazocine, although this opioid receptor agonist induces nitric oxide/cGMP pathway activation. (C) 2004 Elsevier B.V. All rights reserved.