Antinociceptive action of epidural K+(ATP) channel openers via interaction with morphine and an alpha(2)- adrenergic agonist in rats

Potassium (K(+)) channels may play some role in the analgesic actions of mu-opioid agonists and alpha(2)-adrenergic agonists (alpha(2) agonists). We examined whether the adenosine triphosphate-sensitive K(+)(K(+)(ATP)) channel openers, levcromakalim and nicorandil, (given epidurally), might have antinociceptive effects in a tail flick test in adult male Sprague-Dawley rats implanted with a lumbar epidural catheter. The interactions with morphine and an alpha(2) agonist were also examined. The epidural administration of levcromakalim (10 microg, 100 microg) or nicorandil (10 microg, 100 microg) alone did not produce antinociception, but 100 microg levcromakalim or nicorandil did potentiate the antinociceptive effect induced by epidural morphine. Epidural glibenclamide (10 microg), a K(+)(ATP) channel blocker, or naloxone (10 microg) antagonized this potentiation. Systemic administration of levcromakalim or nicorandil (at the same dose as that given into the epidural space) did not potentiate the epidural morphine-induced analgesia. A combination of epidural dexmedetomidine (1 microg) and morphine (1 microg) (each at a subantinociceptive dose) had a significant antinociceptive effect, and epidural glibenclamide (10 microg) partly antagonized this antinociception. These data suggest that levcromakalim and nicorandil potentiate the analgesic action of both morphine and dexmedetomidine, probably via an activation of K(+)(ATP) channels at the spinal cord level.