The peripheral antinociceptive effect of nalbuphine is associated with activation of ATP-sensitive K⁺ channels

There is evidence that local peripheral administration of codeine and morphine produces antinociception through the activation of the ATP-sensitive K⁺-channel. Therefore we evaluated the participation of this channel in the antinociceptive action produced by nalbuphine in the formalin test. Female Wistar rats (160-200 g) were injected in the dorsal surface of the right hind paw with 50 μl of formalin (5%). Nociception was quantified as the number of flinches of the injected paw during 1 hr, whereas a reduction of the number of flinches was considered antinociception. Rats received a s.c. injection (50 μl) into the dorsal surface of the right hind paw of vehicle or increasing doses of nalbuphine (100-400 μg/paw) 20 min before formalin injection into the ipsilateral paw. To determine whether nalbuphine-induced peripheral antinociception was mediated by K⁺-channels, the effect of pretreatment (10 min before formalin injection) with the appropriate vehicle or the ATP-sensitive K⁺-channel inhibitor glibenclamide (25-100 μg/paw) on the antinociceptive effect induced by local peripheral nalbuphine (400 μg/paw) was assessed. Morphine was used as positive antinociceptive control. Local peripheral injection of nalbuphine produced a dose-dependent antinociception during both phases of the test. Local pretreatment with glibenclamide prevented nalbuphine-induced antinociception in a dose-dependent fashion in both phases of the test. Our data suggest that nalbuphine activates ATP-sensitive K⁺-channels in order to produce its peripheral antinociceptive effect.