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 micro-
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 microg) dose-dependently reversed the
hyperalgesia induced in the rat paw by local injection of
carrageenan (250 microg) or
prostaglandin E(2) (2 microg), measured by the paw pressure test. Using the selective
kappa-opioid receptor antagonist
nor-binaltorphimine (
Nor-BNI, 200 microg/paw), it was confirmed that
bremazocine (50 microg/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 microg) and
tolbutamide (40, 80 and 160 microg) did not antagonise the antinociceptive effect of
bremazocine (50 microg). The same results were obtained when we used
prostaglandin E(2) (2 microg) as the hyperalgesic stimulus. The supposed participation of other types of K(+) channels was tested using the Ca(2+)-activated K(+) channel blockers
dequalinium (12.5, 25 and 50 microg) and
charybdotoxin (0.5, 1 and 2 microg) and different types of the non-selective K(+) channel blockers
tetraethylammonium (25, 50 and 100 microg) and
4-aminopyridine (10, 25 and 50 microg). 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.