title: 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: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Pain & Neurology, Medicinal Research Laboratories, Shionogi Co., Ltd., Osaka, Japan; Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakamura
authors.forename: Masahide
authors.initials: M
authors.lastname: Fujita
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ono
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Hongo
authors.forename: Tomoe
authors.initials: T
authors.lastname: Kanbara
authors.forename: Koichi
authors.initials: K
authors.lastname: Ogawa
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Morioka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nishiyori
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shibasaki
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Mori
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Gaku
authors.initials: G
authors.lastname: Sakaguchi
authors.forename: Akira
authors.initials: A
authors.lastname: Kato
authors.forename: Minoru
authors.initials: M
authors.lastname: Hasegawa
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D059350:Chronic Pain / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology*; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D059225:Nociception / Q000187:drug effects*; D010098:Oxycodone / Q000008:administration & dosage / Q000494:pharmacology*; D010147:Pain Measurement; D026902:Potassium Channel Blockers / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497067:Kcnj3 protein, mouse; D009294:Narcotics; D026902:Potassium Channel Blockers; D034741:RNA, Small Interfering; D009020:Morphine; D010098:Oxycodone
keywords: G protein-gated inwardly rectifying potassium channel; antinociception; morphine; oxycodone; μ-opioid receptor