title: Morphine and oxycodone, but not fentanyl, exhibit antinociceptive effects mediated by G-protein inwardly rectifying potassium (GIRK) channels in an oxaliplatin-induced neuropathy rat model.
abstract: It has begun to be understood that μ-opioid receptor (MOR) produces ligand-biased agonism, which contributes to differential physiological functions of MOR agonists. We previously demonstrated that in oxaliplatin-induced neuropathy in rats, morphine and oxycodone exhibited antinociceptive effects while antinociception of fentanyl was partial, and such different efficacies might result from the different level of Gi/o protein activation. Based on our background, to reveal further mechanism, we focused on the role of Gi/o protein-related downstream signaling, the G-protein inwardly rectifying K(+)1 (GIRK1) channel. The GIRK1 channel blocker tertiapin-Q (30pmol) was intracerebroventricularly (i.c.v.) or intrathecally (i.t.) administered to rats with oxaliplatin-induced neuropathy. The antinociception of systemic morphine (3mg/kg, subcutaneously (s.c.)) was suppressed only by pretreatment of i.t. tertiapin-Q, while supraspinal tertiapin-Q suppressed only the antinociception of systemic oxycodone (0.56mg/kg, s.c.). Partial antinocicpetion of fentanyl (0.017mg/kg, s.c.) was neither affected by i.c.v nor i.t. tertiapin-Q. These results demonstrated that GIRK1 channels differentially contribute to antinociceptive effects of MOR agonists, and that action site of GIRK1 channels is also different between morphine and oxycodone in oxaliplatin model. This study suggests the possibility that GIRK1 channels have a crucial role for antinociception of MOR agonists in oxaliplatin-induced neuropathy.
authors.affiliation: Pain & Neurology, Discovery Research Laboratories, SHIONOGI Co., Ltd., 1-1, 3-chome, Futaba-cho, Toyonaka 561-0825, Osaka, Japan; Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Tomoe
authors.initials: T
authors.lastname: Kanbara
authors.affiliation: Pain & Neurology, Discovery Research Laboratories, SHIONOGI Co., Ltd., 1-1, 3-chome, Futaba-cho, Toyonaka 561-0825, Osaka, Japan; Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shibasaki
authors.affiliation: Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Mori
authors.affiliation: Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Pain & Neurology, Discovery Research Laboratories, SHIONOGI Co., Ltd., 1-1, 3-chome, Futaba-cho, Toyonaka 561-0825, Osaka, Japan.
authors.forename: Gaku
authors.initials: G
authors.lastname: Sakaguchi
authors.affiliation: Pain & Neurology, Discovery Research Laboratories, SHIONOGI Co., Ltd., 1-1, 3-chome, Futaba-cho, Toyonaka 561-0825, Osaka, Japan. Electronic address: toshiyuki.kanemasa@shionogi.co.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kanemasa
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D005283:Fentanyl / Q000627:therapeutic use*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism*; D008297:Male; D009020:Morphine / Q000627:therapeutic use*; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D010098:Oxycodone / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists*
chemical_list: D000701:Analgesics, Opioid; D000970:Antineoplastic Agents; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D009944:Organoplatinum Compounds; D017450:Receptors, Opioid, mu; D000077150:Oxaliplatin; D009020:Morphine; D010098:Oxycodone; D005283:Fentanyl
keywords: Antinociception; G-protein inwardly rectifying K(+) channel; MOR agonists; Neuropathy; Oxaliplatin