title: Suppression of the acute upregulation of phosphorylated-extracellular regulated kinase in ventral tegmental area by a μ-opioid receptor agonist is related to resistance to rewarding effects in a mouse model of bone cancer.
abstract: We investigated the mechanisms underlying the suppression of the rewarding effects of opioids using the femur bone cancer (FBC) mouse model. The rewarding and antinociceptive effects of subcutaneously administered morphine and oxycodone in the FBC model mice were assessed using the conditioned place preference test and the von-Frey test. In FBC mice, antinociceptive doses of morphine (30 mg/kg) and oxycodone (5 mg/kg) did not produce the rewarding effects but excessive doses of morphine (300 mg/kg) and oxycodone (100 mg/kg) did. Western blot analyses revealed a transient and significant increase in phosphorylated-extracellular regulated kinase (p-ERK) levels in ventral tegmental area (VTA) 5 min after the administration of morphine in sham-group. Interestingly, in FBC group, a regular dose of morphine did not increase p-ERK levels but a high dose of morphine caused an increase in p-ERK level 5 min after administration. The rewarding effects of a regular dose of and a high dose of morphine in the sham-operation and FBC model, respectively, were significantly inhibited by the MEK inhibitor. The suppression of p-ERK might result in resistance to these rewarding effects under the conditions of bone cancer.
authors.affiliation: Pain & Neuroscience, Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., 1-1, 3-chome, Futaba-cho, Toyonaka, Osaka 561-0825, Japan. Electronic address: atsushi_nakamura@shionogi.co.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Pain & Neuroscience, Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., 1-1, 3-chome, Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ono
authors.affiliation: Pain & Neuroscience, Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., 1-1, 3-chome, Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Ando
authors.affiliation: Pain & Neuroscience, Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., 1-1, 3-chome, Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Mikie
authors.initials: M
authors.lastname: Hinata
authors.affiliation: Pain & Neuroscience, Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., 1-1, 3-chome, Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Niidome
authors.affiliation: Pain & Neuroscience, Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., 1-1, 3-chome, Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Omachi
authors.affiliation: Pain & Neuroscience, Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., 1-1, 3-chome, Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Gaku
authors.initials: G
authors.lastname: Sakaguchi
authors.affiliation: Pain & Neuroscience, Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., 1-1, 3-chome, Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Shinohara
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D010098:Oxycodone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011869:Radioligand Assay; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D012201:Reward; D015854:Up-Regulation / Q000187:drug effects*; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D000700:Analgesics; D002070:Butadienes; D009570:Nitriles; D017450:Receptors, Opioid, mu; C113580:U 0126; D009020:Morphine; D010098:Oxycodone; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Antinociception; Bone cancer pain; Extracellular regulated kinase; Opioid; Rewarding effect