The role of ATP-dependent K+ channels in antinociception, tolerance and morphine dependence

  Tolerance and dependence are two main problems that have limited morphine administration as an analgesic drug and they might be as a result of changes in the number and affinity of receptors, dysfunction of adenylate cyclase, impaired coupling between activated µ receptor and K+ channels, and changes in the K+ and Ca2+ channels. There are several reports concerning the role of some of these factors in the occurrence of tolerance and dependence. It has been suggested that KATP channels are involved in morphine-induced analgesia. In this study the effect of a constitutive KATP opening state by chronic administration of minoxidil (a KATP opener) on morphine tolerance and dependence was studied using tail-flick test. A single dose (5 mg/kg) of morphine, but not its chronic administration produced analgesia (p<0.001). In addition single and chronic (2 mg/kg) administration of minoxidil produced analgesia (p<0.0001 vs ethanol) and chronic co-administration of morphine and minoxidil did not reduce morphine tolerance, while It reduced jumping (p<0.01) and weight loss (p<0.05) as signs of dependence. Naloxone did not antagonize minoxidil analgesia. Morphine analgesia was reduced by glibenclamide 2 mg/kg (p<0.001). These results may suggest that co-administration of morphine and minoxidil is able to reduce some dependence signs of morphine. Since this treatment reduced the jumping and weight loss, but not the writhing sign, it is concluded that different mechanisms and sites of action are involved in the development of each of the dependence signs.