G protein-gated inwardly rectifying potassium (KIR3) channels play a primary role in the antinociceptive effect of oxycodone, but not morphine, at supraspinal sites.

Abstract

BACKGROUND AND PURPOSE:

Oxycodone and morphine are μ-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 (K(IR)3 also known as GIRK) channels in their antinociceptive effects.

EXPERIMENTAL APPROACH:

Opioid-induced antinociceptive effects were assessed in mice, using the tail-flick test, by i.c.v. and intrathecal (i.t.) administration of morphine and oxycodone, alone and following inhibition of K(IR)3.1 channels with tertiapin-Q (30 pmol per mouse, i.c.v. and i.t.) and K(IR)3.1-specific siRNA. The antinociceptive effects of oxycodone and morphine were also examined after tertiapin-Q administration in the mouse femur bone cancer and neuropathic pain models.

KEY RESULTS:

The antinociceptive effects of oxycodone, after both i.c.v. and i.t. administrations, were markedly attenuated by K(IR)3.1 channel inhibition. In contrast, the antinociceptive effects of i.c.v. morphine were unaffected, whereas those induced by i.t. morphine were attenuated, by K(IR)3.1 channel inhibition. In the two chronic pain models, the antinociceptive effects of s.c. oxycodone, but not morphine, were inhibited by supraspinal administration of tertiapin-Q.

CONCLUSION AND IMPLICATIONS:

These results demonstrate that K(IR)3.1 channels play a primary role in the antinociceptive effects of oxycodone, but not those of morphine, at supraspinal sites and suggest that supraspinal K(IR)3.1 channels are responsible for the unique analgesic profile of oxycodone.

• Authors: Atsushi Nakamura, Masahide Fujita, Hiroko Ono, Yoshie Hongo, Tomoe Kanbara, Koichi Ogawa, Yasuhide Morioka, Atsushi Nishiyori, Masahiro Shibasaki, Tomohisa Mori, Tsutomu Suzuki, Gaku Sakaguchi, Akira Kato, Minoru Hasegawa
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 171 Issue 1 Pg. 253-64 (Jan 2014) ISSN: 1476-5381 [Electronic] England
• PMID: 24117458 (Publication Type: Comparative Study, Journal Article)
• Copyright: © 2013 The British Pharmacological Society.

Chemical References

• G Protein-Coupled Inwardly-Rectifying Potassium Channels
• Kcnj3 protein, mouse
• Narcotics
• Potassium Channel Blockers
• RNA, Small Interfering
• Morphine
• Oxycodone

Topics

• Animals
• Brain (drug effects, metabolism)
• Chronic Pain (genetics, metabolism, prevention & control)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• G Protein-Coupled Inwardly-Rectifying Potassium Channels (drug effects, genetics, metabolism)
• Injections, Intraventricular
• Injections, Spinal
• Male
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Morphine (administration & dosage, pharmacology)
• Narcotics (administration & dosage, pharmacology)
• Neuralgia (genetics, metabolism, prevention & control)
• Nociception (drug effects)
• Oxycodone (administration & dosage, pharmacology)
• Pain Measurement
• Potassium Channel Blockers (pharmacology)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Xenopus laevis