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 (KATP) channels in chronic morphine tolerance.
Materials and Methods: Male mice were injected intrathecally with morphine or saline, respectively (each in 10 μL). Different doses of the KATP opener cromakalim (0.3, 1, or 3 μg/10 μL/mouse) were administered 15 minutes before the morphine (10 μg/10 μL/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 (100 mg/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-1β 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 (Kir) 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-1β and the attenuation of morphine chronic antinociceptive tolerance.