Opening of the Adenosine Triphosphate-sensitive Potassium Channel Attenuates Morphine Tolerance by Inhibiting JNK and Astrocyte Activation in the Spinal Cord

Objectives: In the present study, we investigated the role of adenosine triphosphate (ATP)-sensitive potassium (K-ATP) channels in chronic morphine tolerance. Materials and Methods: Male mice were injected intrathecally with morphine or saline, respectively (each in 10 mu L). Different doses of the KATP opener cromakalim (0.3, 1, or 3 mu g/10 mu L/mouse) were administered 15 minutes before the morphine (10 mu g/10 mL/mouse) challenge daily for 7 consecutive days. Half an hour after morphine injection, the tail-flick latency was measured to evaluate the antinociceptive effect of morphine. On the seventh day, mice were euthanized with sodium pentobarbital (100mg/kg) at 1 hour after morphine injection, and their spinal cords were removed for the assays of Western blot, immunofluorescence, and quantitative real- time polymerase chain reaction. Results: Opening of the KATP channel attenuates chronic morphine tolerance, suppresses astrocyte activation inhibits the increase in interleukin-1 beta at the transcriptional and the translational levels, and reduces the upregulation of phosphorylated c-Jun N-terminal kinase mitogen-activated protein kinase in the spinal cord after chronic morphine treatment. Moreover, transcriptional levels of spinal cord astrocyte KATP channel subunits, named the inwardly rectifying potassium (K-ir) 6.1 and sulfonylurea receptor 1, are decreased in morphine-tolerant mice. Discussion: Cromakalim suppresses morphine-induced astrocyte activation significantly by suppressing the c-Jun N-terminal kinase pathway, resulting in a reduced release of interleukin-1 beta and the attenuation of morphine chronic antinociceptive tolerance.