G protein-gated inwardly rectifying potassium (GIRK) channels play a primary role in the antinociceptive effect of oxycodone, but not morphine, at supraspinal sites.

British journal of pharmacology

PubMedID: 24117458

Nakamura A, Fujita M, Ono H, Hongo Y, Kanbara T, Ogawa K, Morioka Y, Nishiyori A, Shibasaki M, Mori T, Suzuki T, Sakaguchi G, Kato A, Hasegawa M. G protein-gated inwardly rectifying potassium (GIRK) channels play a primary role in the antinociceptive effect of oxycodone, but not morphine, at supraspinal sites. Br J Pharmacol. 2013;.
BACKGROUND AND PURPOSE
Oxycodone and morphine are ยต-opioid receptor agonists prescribed to control moderate to severe pain. Previous studies suggested that these opioids exhibit different analgesic profiles. We hypothesized that distinct mechanisms mediate the differential effects of these two opioids and investigated the role of G protein-gated inwardly rectifying potassium (GIRK) channels in their antinociceptive effects.

EXPERIMENTAL APPROACH
Opioid-induced antinociceptive effects were assessed by intracerebroventricular (i.c.v.) and intrathecal (i.t.) administration following inhibition of GIRK1 channels with tertiapin-Q (30 pmol/mouse, i.c.v., and i.t.) and GIRK1-specific siRNA using the mouse tail-flick test. The antinociceptive effects of oxycodone and morphine were also examined after tertiapin-Q administration using mouse femur bone cancer and neuropathic pain models.

KEY RESULTS
The antinociceptive effects of oxycodone with both i.c.v. and i.t. administration were markedly attenuated by GIRK1 channel inhibition. In contrast, i.c.v. morphine administration was insensitive to GIRK1 channel inhibition, while i.t. administration of morphine was attenuated. In the two chronic pain models, the antinociceptive effect of subcutaneous oxycodone administration, but not morphine, was inhibited by supraspinal administration of tertiapin-Q.

CONCLUSION AND IMPLICATIONS
The results demonstrated that GIRK1 channels play a primary role in the antinociceptive effects of oxycodone, but not morphine, at supraspinal sites, and suggested that supraspinal GIRK1 channels are responsible for the unique analgesic profile of oxycodone.