2003 Fiscal Year Annual Research Report

がん疼痛へのモルヒネ鎮痛効果と副作用出現の分子遺伝学的研究

Research Project

Project/Area Number	15025206
Research Institution	Tohoku University
Principal Investigator	曽良一郎東北大学, 大学院・医学系研究科, 教授 (40322713)
Co-Investigator(Kenkyū-buntansha)	池田和隆 (財)東京都医学研究機構, 東京都精神医学総合研究所, 副参事研究員 (60281656) 高橋雅彦東北大学, 大学院・医学系研究科, 助教授 (60236320) 沼知陽太郎東北大学, 大学院・医学系研究科, 助教授 (00261636) 下山恵美千葉大学, 大学院・医学研究院, 講師 (10206253) 倉石泰富山医科薬科大学, 薬学部, 教授 (80111970)
Keywords	ミューオピオイド受容体 / トランスジェニックマウス / 耐性形成 / 身体依存 / メラノーマ
Research Abstract	激烈な疼痛に対する第一選択の鎮痛薬は、いまだ強力な鎮痛作用を持つモルヒネに代表されるオピオイド類であり、WHOがん疼痛治療指針が発表されてから、モルヒネを中心としたがん疼痛治療が普及してきている。しかし、モルヒネの鎮痛効果や依存、耐性などの副作用出現には個人差があり、臨床上、効果的な疼痛治療を妨げている大きな原因の一つである。本研究ではオーダーメイドのがん疼痛治療への道を拓くことを目的として以下の研究を行った。日本人におけるミューオピオイド受容体(μOR)のゲノム配列に存在する遺伝子多型を解析し広い領域にわたり連鎖不平衡にあることを確認した。ヒトμOR遺伝子多型とモルヒネの副作用と関連する薬物依存とは統計的に有意な関連が明らかとなったことから特許申請を行った。がん疼痛の症例ではモルヒネの鎮痛効果との関連は明らかにすることはできなかったが、癌腫の種類あるいは骨転移などの進展度、部位等の因子により、がん疼痛の強度が影響されることが考えられることから、さらに症例を増やして検討するため、新たに研究協力病院を追加した。また、μORとモルヒネ治療の代表的な副作用である耐性、身体依存の関係をより詳細に検討するためにノルアドレナリン神経系のみに選択的にμORを過剰発現したトランスジェニック(Tg)マウスを作製した。疼痛閾値変化、耐性形成並びに身体依存形成において野生型とTgマウス、並びにμOR-KOマウスとμOR-KO-Tgマウスとの間に有意な差は認められなかった。しかし、μOR-KOマウスにおいて有意に低下しているストレス負荷後の血漿中コルチコステロン濃度の上昇の程度が、μOR-KO-Tgマウスでは野生型レベルまで復帰していることが明らかとなった。メラノーマを用いたがん疼痛モデルにおいては、Gabapentinがアロディニアと機械刺激に対する疼痛閾値の低下に対して有効であった。

Research Products

(37 results)

All Other

All Publications (37 results)

[Publications] Murphy DL, et al.: "Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders."Genes Brain Behav. 2(6). 350-364 (2003)
[Publications] Hall FS, et al.: "Sex-dependent modulation of ethanol consumption in vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) knockout mice."Neuropsychopharmacology. 28. 620-628 (2003)
[Publications] Hall FS, et al.: "Congenic C57BL/6 mu opiate receptor (MOR) knockout mice : baseline and opiate effects."Genes Brain Behav. 2. 114-121 (2003)
[Publications] Yuyama K, et al.: "Overexpression of V-1 prevents NO-induced cell death : involvement of enhanced tetrahydrobiopterin (BH_4) biosynthesis."J Neurosci Res. 72(6). 716-725 (2003)
[Publications] Yuyama K, et al.: "Caspase-independent cell death by low concentrations of nitric oxide (NO) in PC12 cells : involvement of the inhibition of cytochrome C oxidase and the production of reactive oxygen species (ROS) in mitochondria."J Neurosci Res. 73(3). 351-363 (2003)
[Publications] Itokawa M, et al.: "Association between a novel polumorphism in the promoter region of the neuropeptide Y gene and schizophrenia in humans."Neurosci Lett. 347. 202-204 (2003)
[Publications] Ujike H, et al.: "Nine-or fewer repeat alleles in VNTR polymorphism of the dopamine transporter gene is a strong risk factor for prolonged methamphetamine psychosis."Pharmacogenomics J. 3(4). 242-247 (2003)
[Publications] Mizoguchi H, et al.: "Lack of the mu-opioid receptor-mediated G-protein activation in the mouse spinal cord lacking exonl and exon 2 & 3 of MOR-1 gene."J Pharmacol Sci. 93. 423-429 (2003)
[Publications] Shen H, et al.: "Electroconvulsive shock increases serotonin transporter in the rat frontal cortex."Neurosci Lett. 341(2). 170-172 (2003)
[Publications] Kabbaj M, et al.: "Methamphetamine differentially regulates hippocampal glucocorticoid and mineralocorticoid receptors mRNAs in Fisher and Lewis rats."Brain Res Mol Brain Res. 117(1). 8-14 (2003)
[Publications] Kobayashi T, et al.: "Inhibition of G protein-activated inwardly rectifying K+ channels by fluoxetine (Prozac)."Br J Pharmacol. 138. 1119-1128 (2003)
[Publications] Sasaki A, et al.: "Roles of alpha-adrenoceptors and sympathetic nerve in acute herpetic pain induced by herpes simplex virus inoculation in mice."J Pharmacol Sci. 192(4). 329-336 (2003)
[Publications] Zhang HW, et al.: "Mechanical hypersensitivity and alterations in cutaneous nerve fibers in a mouse model of skin cancer pain."J Pharmacol Sci. 91(2). 167-170 (2003)
[Publications] Kuraishi Y, et al.: "Suppression by gabapentin of pain-related mechano-responses in mice given orthotopic tumor inoculation."Biol Pharm Bull. 26(4). 550-552 (2003)
[Publications] Hall FS, et al.: "Mu opioid receptor knockout mice display reduced cocaine conditioned place preference but enhanced sensitization of cocaine induced locomotion."Brain Res. 121(1-2). 123-130 (2003)
[Publications] Yamamoto H, et al.: "Changes in expression of the mouse homologues of KIAA genes after subchronic methamphetamine treatment."Ann New York Acad Sci. in press. (2004)
[Publications] Han W, et al.: "A possible genetic mechanism underlying individual and interstrain differences in opioid actions : focus on the mu opioid receptor gene."Ann New York Acad Sci. in press. (2004)
[Publications] Ide S, et al.: "Gene polymorphisms of the mu opioid receptor in methamphetamine abusers."Ann New York Acad Sci. in press. (2004)
[Publications] Hironaka N, et al.: "Food-reinforced operant behavior in dopamine transporter knockout mice : enhanced resistance to extinction."Ann New York Acad Sci. in press. (2004)
[Publications] Kobayashi H, et al.: "Association study between alfa-synuclein gene polymorphism and methamphetamine dependence."Ann New York Acad Sci. in press. (2004)
[Publications] Harano M, et al.: "TaqI A polymorphism of DRD2 gene and brain atrophy in methamphetamine psychosis."Ann New York Acad Sci. in press. (2004)
[Publications] Inada T, et al.: "No association between the type 1 sigma receptor gene polymorphisms and methamphetamine abuse in the Japanese population : A collaborative study by the Japanese Genetics Initiative for Drug Abuse (JGIDA)."Ann New York Acad Sci. in press. (2004)
[Publications] Iwata N, et al.: "No association between the candidate genes of t-PA/Plasminogen system and Japanese methamphetamine related disorder : A collaborative study by the Japanese Genetics Initiative for Drug Abuse (JGIDA)."Ann New York Acad Sci. in press. (2004)
[Publications] Numachi Y, et al.: "Psychostimulant alters expression of DNA methyltransferase mRNA in the rat brain."Ann New York Acad Sci. in press. (2004)
[Publications] Hall FS, et al.: "The molecular mechanisms underlying the rewarding effects of cocaine."Ann New York Acad Sci. in press. (2004)
[Publications] Shen H, et al.: "Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters."Neuropsychopharmacology. in press. (2004)
[Publications] Yamamoto T, et al.: "Functional identification of ASCTI neutral amino acid transporter as thepredominant system for the uptake of L-serine in rat neurons in primaryculture."Neurosci Res. in press. (2004)
[Publications] Ide S, et al.: "Buprenorphine antinociception is abolished, but naloxone-sensitive reward is retained, in mu-opioid receptor knockout mice."Neuropsychopharmacology. in press. (2004)
[Publications] Mansikka H, et al.: "Nerve injury induces a tonic bilateral : mu-opioid receptor mediated inhibitory effect on mechanical allodynia in mice."Anesthesiology. in press. (2004)
[Publications] Takasaki I, et al.: "Suppression of acute herpetic pain-related responses by the {kappa}-opioid receptor agonist TRK-820 in mice."J Pharmacol Exp Ther. in press. (2004)
[Publications] 沼知陽太郎, 他: "うつと不安の共通因子"Bulletin of Depression and Anxiety. 1. 8-11 (2003)
[Publications] 曽良一郎, 他: "カテコラミントランスポーターと高次神経機能"自律神軽. 40. 238-243 (2003)
[Publications] 糸川昌成, 他: "DNAマイクロアレイを出発点とした統合失調症の病態に関与する遺伝子の研究"精神神経学雑誌. 106(1). 42-48 (2004)
[Publications] 沼知陽太郎, 他: "覚醒剤の体内動態と脳内分布"Clinical Neuroscience. in press. (2004)
[Publications] 沼知陽太郎, 他: "ストレス逆耐性仮説"こころの臨床. in press. (2004)
[Publications] Sora I, et al.: "Opioid Research : Methods and Protocols"Zhizhong Z.Pan, Humana Press. 12 (2003)
[Publications] Ikeda K, et al.: "Opioid Research : Methods and Protocols"Zhizhong Z.Pan, Humana Press. 12 (2003)

2003 Fiscal Year Annual Research Report

がん疼痛へのモルヒネ鎮痛効果と副作用出現の分子遺伝学的研究

Principal Investigator

曽良 一郎 東北大学, 大学院・医学系研究科, 教授 (40322713)

Research Products

[Publications] Murphy DL, et al.: "Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders."Genes Brain Behav. 2(6). 350-364 (2003)

[Publications] Hall FS, et al.: "Sex-dependent modulation of ethanol consumption in vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) knockout mice."Neuropsychopharmacology. 28. 620-628 (2003)

[Publications] Hall FS, et al.: "Congenic C57BL/6 mu opiate receptor (MOR) knockout mice : baseline and opiate effects."Genes Brain Behav. 2. 114-121 (2003)

[Publications] Yuyama K, et al.: "Overexpression of V-1 prevents NO-induced cell death : involvement of enhanced tetrahydrobiopterin (BH_4) biosynthesis."J Neurosci Res. 72(6). 716-725 (2003)

[Publications] Yuyama K, et al.: "Caspase-independent cell death by low concentrations of nitric oxide (NO) in PC12 cells : involvement of the inhibition of cytochrome C oxidase and the production of reactive oxygen species (ROS) in mitochondria."J Neurosci Res. 73(3). 351-363 (2003)

[Publications] Itokawa M, et al.: "Association between a novel polumorphism in the promoter region of the neuropeptide Y gene and schizophrenia in humans."Neurosci Lett. 347. 202-204 (2003)

[Publications] Ujike H, et al.: "Nine-or fewer repeat alleles in VNTR polymorphism of the dopamine transporter gene is a strong risk factor for prolonged methamphetamine psychosis."Pharmacogenomics J. 3(4). 242-247 (2003)

[Publications] Mizoguchi H, et al.: "Lack of the mu-opioid receptor-mediated G-protein activation in the mouse spinal cord lacking exonl and exon 2 & 3 of MOR-1 gene."J Pharmacol Sci. 93. 423-429 (2003)

[Publications] Shen H, et al.: "Electroconvulsive shock increases serotonin transporter in the rat frontal cortex."Neurosci Lett. 341(2). 170-172 (2003)

[Publications] Kabbaj M, et al.: "Methamphetamine differentially regulates hippocampal glucocorticoid and mineralocorticoid receptors mRNAs in Fisher and Lewis rats."Brain Res Mol Brain Res. 117(1). 8-14 (2003)

[Publications] Kobayashi T, et al.: "Inhibition of G protein-activated inwardly rectifying K+ channels by fluoxetine (Prozac)."Br J Pharmacol. 138. 1119-1128 (2003)

[Publications] Sasaki A, et al.: "Roles of alpha-adrenoceptors and sympathetic nerve in acute herpetic pain induced by herpes simplex virus inoculation in mice."J Pharmacol Sci. 192(4). 329-336 (2003)

[Publications] Zhang HW, et al.: "Mechanical hypersensitivity and alterations in cutaneous nerve fibers in a mouse model of skin cancer pain."J Pharmacol Sci. 91(2). 167-170 (2003)

[Publications] Kuraishi Y, et al.: "Suppression by gabapentin of pain-related mechano-responses in mice given orthotopic tumor inoculation."Biol Pharm Bull. 26(4). 550-552 (2003)

[Publications] Hall FS, et al.: "Mu opioid receptor knockout mice display reduced cocaine conditioned place preference but enhanced sensitization of cocaine induced locomotion."Brain Res. 121(1-2). 123-130 (2003)

[Publications] Yamamoto H, et al.: "Changes in expression of the mouse homologues of KIAA genes after subchronic methamphetamine treatment."Ann New York Acad Sci. in press. (2004)

[Publications] Han W, et al.: "A possible genetic mechanism underlying individual and interstrain differences in opioid actions : focus on the mu opioid receptor gene."Ann New York Acad Sci. in press. (2004)

[Publications] Ide S, et al.: "Gene polymorphisms of the mu opioid receptor in methamphetamine abusers."Ann New York Acad Sci. in press. (2004)

[Publications] Hironaka N, et al.: "Food-reinforced operant behavior in dopamine transporter knockout mice : enhanced resistance to extinction."Ann New York Acad Sci. in press. (2004)

[Publications] Kobayashi H, et al.: "Association study between alfa-synuclein gene polymorphism and methamphetamine dependence."Ann New York Acad Sci. in press. (2004)

[Publications] Harano M, et al.: "TaqI A polymorphism of DRD2 gene and brain atrophy in methamphetamine psychosis."Ann New York Acad Sci. in press. (2004)

[Publications] Inada T, et al.: "No association between the type 1 sigma receptor gene polymorphisms and methamphetamine abuse in the Japanese population : A collaborative study by the Japanese Genetics Initiative for Drug Abuse (JGIDA)."Ann New York Acad Sci. in press. (2004)

[Publications] Iwata N, et al.: "No association between the candidate genes of t-PA/Plasminogen system and Japanese methamphetamine related disorder : A collaborative study by the Japanese Genetics Initiative for Drug Abuse (JGIDA)."Ann New York Acad Sci. in press. (2004)

[Publications] Numachi Y, et al.: "Psychostimulant alters expression of DNA methyltransferase mRNA in the rat brain."Ann New York Acad Sci. in press. (2004)

[Publications] Hall FS, et al.: "The molecular mechanisms underlying the rewarding effects of cocaine."Ann New York Acad Sci. in press. (2004)

[Publications] Shen H, et al.: "Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters."Neuropsychopharmacology. in press. (2004)

[Publications] Yamamoto T, et al.: "Functional identification of ASCTI neutral amino acid transporter as thepredominant system for the uptake of L-serine in rat neurons in primaryculture."Neurosci Res. in press. (2004)

[Publications] Ide S, et al.: "Buprenorphine antinociception is abolished, but naloxone-sensitive reward is retained, in mu-opioid receptor knockout mice."Neuropsychopharmacology. in press. (2004)

[Publications] Mansikka H, et al.: "Nerve injury induces a tonic bilateral : mu-opioid receptor mediated inhibitory effect on mechanical allodynia in mice."Anesthesiology. in press. (2004)

[Publications] Takasaki I, et al.: "Suppression of acute herpetic pain-related responses by the {kappa}-opioid receptor agonist TRK-820 in mice."J Pharmacol Exp Ther. in press. (2004)

[Publications] 沼知陽太郎, 他: "うつと不安の共通因子"Bulletin of Depression and Anxiety. 1. 8-11 (2003)

[Publications] 曽良一郎, 他: "カテコラミントランスポーターと高次神経機能"自律神軽. 40. 238-243 (2003)

[Publications] 糸川昌成, 他: "DNAマイクロアレイを出発点とした統合失調症の病態に関与する遺伝子の研究"精神神経学雑誌. 106(1). 42-48 (2004)

[Publications] 沼知陽太郎, 他: "覚醒剤の体内動態と脳内分布"Clinical Neuroscience. in press. (2004)

[Publications] 沼知陽太郎, 他: "ストレス逆耐性仮説"こころの臨床. in press. (2004)

[Publications] Sora I, et al.: "Opioid Research : Methods and Protocols"Zhizhong Z.Pan, Humana Press. 12 (2003)

[Publications] Ikeda K, et al.: "Opioid Research : Methods and Protocols"Zhizhong Z.Pan, Humana Press. 12 (2003)

曽良一郎東北大学, 大学院・医学系研究科, 教授 (40322713)