Involvement of ATP-sensitive potassium channels and the opioid system in the anticonvulsive effect of zolpidem in mice

Zolpidem is a hypnotic medication that mainly exerts its function through activating gamma-aminobutyric acid (GABA)(A) receptors. There is some evidence that zolpidem may have anticonvulsive effects. However, the mechanisms underlying this effect have not been elucidated yet. In the present study, we used the pentylentetrazole (PTZ)-induced generalized seizure model in mice to investigate whether zolpidem can affect seizure threshold. We also further evaluated the roles of ATP-sensitive potassium (K-ATP) channels as well as mu-opioid receptors in the effects of zolpidem on seizure threshold. Our data showed that zolpidem in a dose-dependent manner increased the VIZ-induced seizure threshold. The noneffective (i.e., did not significantly alter the PTZ-induced seizure threshold by itself) doses of K-ATP channel blocker (glibenclamide) and nonselective opioid receptor antagonist (naloxone) were able to inhibit the anticonvulsive effect of zolpidem. Additionally, noneffective doses of either K-ATP, channel opener (cromakalim) or nonselective mu-opioid receptor agonist (morphine) in combination with a noneffective dose of zolpidem exerted a significant anticonvulsive effect on PTZ-induced seizures in mice. A combination of noneffective doses of naloxone and glibenclamide, which separately did not affect zolpidem effect on seizure threshold, inhibited the anticonvulsive effects of zolpidem. These results suggest a role for K-ATP channels and the opioid system, alone or in combination, in the anticonvulsive effects of zolpidem. (C) 2016 Elsevier Inc. All rights reserved.