一次求心性C線維の神経回路と機能的意義

1993 Fiscal Year Annual Research Report

• Project/Area Number: 04255103
• Research Institution: Nagoya University
• Principal Investigator: 熊澤 孝朗 名古屋大学, 環境医学研究所, 教授 (20022775)
• Co-Investigator(Kenkyū-buntansha): 堀 哲郎 九州大学, 医学部, 教授 (00022814) ; 東田 陽博 金沢大学, 医学部, 教授 (30093066) ; 成宮 周 京都大学, 医学部, 教授 (70144350) ; 佐藤 公道 京都大学, 薬学部, 教授 (80025709) ; 佐藤 昭夫 (財)東京都老人総合研究所, 自律神経部門, 副所長兼部長 (60072980)
• Keywords: 一次求心性C線維 / 痛覚 / 受容体クローニング / ブラジキニン / ブロスタグランジン / オピオイド / 神経伝達物質 / 細胞内シグナル伝達

Research Abstract

本年度の研究では、末梢及び中枢での痛みの伝達機構を電気生理学的、免疫組織学的、生化学的手法を用いて総合的に調べ、以下の結果を得た。課題7では、PGE_2によるポリモーダル受容器の熱反応増強効果はEP_2受容体を介し、cAMPを増大させて起こることを明らかにした(熊澤)。またBKのB_2受容体遺伝子をクローニングし、BKによりIP_3を介する過分極性のCa^<2+>流入機構をも見い出した(東田)。さらにPGE受容体サブタイプEP_1、EP_2の構造、分布、リガンド結合の特異性と情報伝達を明らかにし、痛覚に関与する後根神経節の小型ニューロンにEP_3受容体が発現していることを見い出した(成宮)。課題8では、体性感覚刺激により交感神経活動に反射電位が観察され、これはオピオイドμ-受容体により抑制されることを見い出した(佐藤昭)。課題9では、痛覚に関与する無髄神経線維の脊髄内終末はSP、CGRP陽性で(杉浦)、脊髄後角のGABA受容体分布は、膠様質ではB型が豊富で、第II、III層ではA型が優勢であることを見い出した(木村)。またμ-及びκ-オピオイド受容体cDNAをクローニングし、持続的疼痛により脊髄I、II層において、μ-及びκ-オピオイド受容体mRNAの発現量が多くなっているという知見を得た(佐藤公)。さらに脊髄視床路切断により視床のSP含有量が低下することより、SPが脊髄視床路の神経伝達物質の1つである可能性を見いだした(金澤)。課題10では、上腹部手術時の痛みストレスによる下垂体ホルモン分泌亢進は、上部頚椎レベルでの硬膜外麻酔により遮断されることを明らかにし(森)、IL-1βによる脳内の痛覚増強作用部位が、視床下部視索前野・前視床下部で、IL-1βの痛覚増強作用に関与するPGE_2はEP_3受容体を介することを明らかにした(堀)。

Research Products

• [Publications] Mizumura,K.他: "Spinal termination patterns of canine identified A-delt and C spermatic polymodal receptors traced by intracellular labeling with Phaseolus vulgaris-leucoagglutinin." J.Comp.Neurol.335. 460-468 (1993)
• [Publications] Mizumura,K.他: "Prostaglandin E_2-induced sensitization of the heat response of canine visceral polymodal receptors in vitro" Neurosci.Lett.161. 117-119 (1993)
• [Publications] Kasai,M.他: "Electrophysiological characteristics of dissociated dorsal root ganglion neurones in rat." Environ.Med.37. 59-62 (1993)
• [Publications] Tadaki,E.他: "Interaction between endogenous opioid and endogenous cholecystokinin (CCK) in modulation og cardio-respiratory responses induced by nociceptive muscular afferents in cats." Environ.Med.37. 167-170 (1993)
• [Publications] Yasui,H.他: "Measurement of first pain and second pain in humans." Environ.Med.37. 63-66 (1993)
• [Publications] Mizumura,K.他: "Augmenting effects of cyclic AMP on the heat response of canine testicular polymodal receptors." Neurosci.Lett.162. 75-77 (1993)
• [Publications] Kumazawa,T.他: "Involvement of EP3 subtype of prostaglandin E receptors in PGE2-induced enhancement of the bradykinin response of nociceptors." Brain Res.632. 321-324 (1993)
• [Publications] Sato,J.他: "Adrenergic excitation of cutaneous nociceptors in chronically inflamed rats." Neurosci.Lett.164. 225-228 (1993)
• [Publications] Mizumura,K.他: "Forskolin does not augment the bradykinin response of canine visceral polymodal receptors in vitro." Neurosci.Lett.(印刷中).
• [Publications] Mizumura,K.他: "Histamine-induced sensitization of the heat response of canine visceral polymodal receptors." Neurosci.Lett.(印刷中).
• [Publications] 佐藤純 他: "知覚神経への直接傷害による痛み" 総合臨床. 42. 2851-2855 (1993)
• [Publications] 熊澤孝朗: "疼痛-オピオイド-呼吸抑制" 神経進歩. (印刷中).
• [Publications] Mo,Z-L.,他: "Effects of vasopressin and angiotensin II on neurones in the rat dorsal motor nucleus of the vagus,in vitro." Journal of Physiology(London). 458. 561-577 (1992)
• [Publications] Katafuchi,T.,他: "Roles of sympathetic nervous system in the suppression of cytotoxicity of splenic natural killer cells in the rat." Journal of Physiology(London). 465. 343-357 (1993)
• [Publications] Take,S.,他: "Central interferon alpha inhibits the natural killer cytotoxicity through sympathetic innervation." American Journal of Physiology. 265. R453-R459 (1993)
• [Publications] Oka,T.,他: "Intracerebroventricular injection of interleukin-1 beta induces hyperalgesia in rats." Brain Research. 623. 61-68 (1993)
• [Publications] Katafuchi,T.,他: "Hypothalamic modulation of splenic natural killer cell activity in rats." Journal of Physiology(London). 471. 209-221 (1993)
• [Publications] Shimizu,N.,他: "An IL-1 beta-induced noradrenaline release in the spleen is mediated by brain corticotropin-releasing factor." Brain,Behavior & Immunity. 7(in press). (1993)
• [Publications] Szreder,Z.,他: "Thermoregulatory effect of intracerebral injections of neuropeptide Y in rats at different temperatures." General Pharmacology. 27(in press). (1993)
• [Publications] Oka,T.他: "EP-1 receptor mediation of prostaglandin E2-induced hyperthermia in rats." American Journal of Physiology. (in press). (1994)
• [Publications] Ichijo,T.,他: "Central interleukin-1 beta enhances splenic sympathetic nerve activity in rats." Brain Research Bulletin. (in press). (1994)
• [Publications] 堀哲郎,他: "免疫能の中枢神経制御" BIOTHERAPY. 6. 1007-1016 (1992)
• [Publications] 堀哲郎: "神経・内分泌系と免疫系のクロストーク" 細胞. 24. 480-485 (1992)
• [Publications] 堀哲郎: "神経系と免疫系の相互作用" Bio medica. 7. 1348-1351 (1992)
• [Publications] 堀哲郎,他: "人類の温熱応答研究の未来像-生体防御と関連して" 日本生気象学雑誌. 29. 45-48 (1992)
• [Publications] 堀哲郎,他: "脳・免疫連関機構からみたストレス・免疫系修飾." ストレス科学. 7. 2-8 (1993)
• [Publications] 堀哲郎: "サイトカインと視床下部機能" 臨床薬理. 11. 145-151 (1993)
• [Publications] 堀哲郎,他: "体温調節のメカニズム" 中毒研究. 6. 227-233 (1993)
• [Publications] 堀哲郎,他: "脳と免疫系" 生体の科学. 44. 548-549 (1993)
• [Publications] 堀哲郎: "脳・免疫連関からみた生体の温熱応答" 日本温泉気候物理医学会雑誌. 57. 29-30 (1993)
• [Publications] Maekawa,K.,他: "In situ hybridization study of μ- and κ-opioid receptor mRNAs in the rat spinal cord and dorsal root ganglia." Neurosci.Lett.(印刷中).
• [Publications] Sugiura Y.,他: "Quantitative analysis of central terminal projections of visceral and somatic unmyelinated (C) primary afferent fibers in the guinea pig." The Journal of Comparative Neurology. 332. 315-325 (1993)
• [Publications] 杉浦康夫: "上皮に属する痛み知覚装置" 綜合臨床. 42(10). 2842-2846 (1993)
• [Publications] Sugimoto,Y,et al.: "Cloning and expression of a cDNA for mouse prostaglandin F receptor." Journal of Biological Chemistry.268. 1356-1360 (1994)
• [Publications] Namba,T.,et al.: "cDNA cloning of a mouse prostacyclin receptor;multiple signalling pathways and expression in thymic medulla." Journal of Biological Chemistry.(印刷中).
• [Publications] Hashi,M.et al: "Ca^<2+> influx evoked by inositol-3,4,5,6-tetrabisphosphate in ras-transformed NIH/3T3 fibroblasts." FEBS Lett.(印刷中).
• [Publications] Black,J.A.et al.: "Cellular localization of voltage-sensitive sodium channels mRNAs I,II and III in the central nervous system." Mol.Brain Res.(印刷中).
• [Publications] Black,J.A.et al.: "Sodium channel mRNAs in cultured spinal cord astrocytes:in situ hybridization in identified cell types." Mol.Brain Res.(印刷中).
• [Publications] Matsuo,A.他: "Immunohistochemical localization in the rat brain of an epitope corresponding to fibroblast growth factor receptor I." Neuroscience. (印刷中).
• [Publications] Kinoshita,T.他: "Histochemical localization of nitric oxide synthase in rat biliary dicts/" Biomed.Res.(印刷中).
• [Publications] Taniguchi,T.他: "Delayed expression of c-fos protein in rat hippocampus and cerebral cortex after transient exposure to hypoxia." Brain Res.(印刷中).
• [Publications] Ding,W.G.他: "Phylogenetic and ontogenic study of neuropeptide Y-containing nerves in the liver." Histochem.J.(印刷中).
• [Publications] Minami,Y.他: "Projection of nitric oxide synthase-containing fibers from the sphemopalatine ganglion to cerebral arteries in the rat" Neuroscience. (印刷中).
• [Publications] Noda,M.et al: "Coupling of m2 and m4 muscarinic actylcholinereceptor subtypes to Ca^<2+>-dependent K^+ channels in transformed NL308" Proc.R.Soc.London B. 251. 215-224 (1993)
• [Publications] Higashida,H.他: "Inositol trisphosphate/Ca^<2+> as a major signal transduction pathway from bradykinin receptors." Jap.J.Physiol.43 Suppl. S95-S99 (1993)
• [Publications] Terasaki,T.et al: "Expression of the Na^<2+> dependent uridine transport system of rabbit small intestine:Studies with mRNA injected Xenopus laevis oocytes." Biol.Pharm.Bull.16. 493-496 (1993)
• [Publications] Kurosawa,M.,他: "Cutaneous mechanical sensory stimulation increases extracellular acetylcholine release in cerebral cortex in anesthetized rats." Neurochemistry International. 21. 423-427 (1992)
• [Publications] Sato,A.,他: "Regulation of regional cerebral blood flow by cholinergic fibers originating in the basal forebrain." Neruoscience Research. 14. 242-274 (1992)
• [Publications] Sato,A.,他: "Mechanism of the reflex inhibition of micturition contractions of the urinary bladder elicited by acupuncture-like stimulation in anesthetized rats." Neuroscience Research. 15. 189-198 (1992)
• [Publications] Adachi,T.,他: "Depending on the mode of application morphine enhances or depresses somatocardiac sympathetic A -and C-reflexes in anesthetized rats." Neuroscience Research. 15. 281-288 (1992)
• [Publications] Cao,W.-H.,他: "Somatosensory regulation of regional hippocampal blood flow in anesthetized rats." Japanese Journal of Physiology. 42. 731-740 (1992)
• [Publications] Hotta,H.,他: "Somatic afferent reguration of plasma prolactin in anesthetized rats." Japanese Journal of Physiology. 43. 501-509 (1993)
• [Publications] Fukuda,K.,他: "Primary structures and expression from C-DNAs of rat opioid receptor delta- and mu- sub・types" FEBS. 327. 311-314 (1993)
• [Publications] Kito,K.,他: "Hepatic energy metabolism during hypotension induced by prostaglandin E_1 and nicardipine in rabbits:an in vivo magnetic resonance spectroscopic study" Anesth.Analy. 77(in press). (1993)
• [Publications] Adachi,T.,他: "Comparison of effects of morphine and CP-96,345,a substance P antagonist,administered intrathecally on the somatosympathetic refelx discharges in anesthetized rats." Regulatory Peptides. 46. 263-265 (1993)
• [Publications] Sato,A.,他: "Neural mechanisms of the reflex inhibition and excitation of gastric motility elicited by acupuncture-like stimulation in anesthetized rats." Neuroscience Research. 18. 53-62 (1993)
• [Publications] Kurosawa,M.,他: "Extracellular release of acetylcholine,noradrenaline and serotonin increases in the cerebral cortex during walking in conscious rats." Neuroscience Letters. 161. 73-76 (1993)
• [Publications] Kurosawa,M.,他: "Cutaneous noxious mechanical sensory stimulation increases extracellular release of noradrenaline and serotonin in the cerebral cortex in anesthetized rats." Biogenic Amines. 10. 27-37 (1993)
• [Publications] Kurosawa,M.,他: "Innocuous mechanical stimulation of the hindlimb skin increases extracellular release of acetylcholine in the cerebral cortex in conscious rats." Biogenic Amines. (印刷中).
• [Publications] Sato,A.,他: "Reflex modulation of gastric and vesical function by acupuncture-like stimulation in anesthetized rats." Biomedical Research. (印刷中).
• [Publications] 森健次郎.他: "痛みのコントロールとQOL" 綜合臨床. 42. 2839-2841 (1993)
• [Publications] Segawa,H.,他: "Anesthesia and Stress Response" Pain Research.8. 1-8 (1993)
• [Publications] Okano,K.,他: "Pharmacological evidence for involvement of excitatory amino acids in aversive responses induced by intrathecal substance P in rats." Biol.Pharm.Bull.16. 861-865 (1993)
• [Publications] Minami,M.,他: "Cloning and expression of a cDNA for the rat〓-opioid receptor." FEBS Lett.329. 291-295 (1993)
• [Publications] Ueda,M.,他: "Detection of capsaicin-evoked release of glutamate from spinal dorsal horn slices of rat with on-line monitoring system." Neurosci.Lett.155. 179-182 (1993)
• [Publications] Minami,M.,他: "In situ hybridization study of〓-opioid receptor mRNA in the rat brain." Neurosci.Lett.162. 161-164 (1993)
• [Publications] Kaneko,S.,他: "Functional expression of Ca^<2+>-mobilizing opioid receptors in Xenopus oocytes injected with rat brain mRNA." Mol.Brain Res.(印刷中).
• [Publications] Minami,M.,他: "Molecular cloning and in situ hybridization histochemistry for rat μ-opioid receptor." Neurosci.Res.(印刷中).
• [Publications] Shirakami,G.: "Central action of C-type natriuretic peptide on vasopressin secretion in conscious rats" Neuroscie Lett.159. 25-28 (1993)
• [Publications] Nishi,M.: "cDNA cloning and pharmacological characterization of an opioid receptor with high affinities for K-subtype-selective ligands" FEBS. 330. 77-80 (1993)
• [Publications] Honda,A.,et al.: "Cloning and expression of a cDNA for mouse prostaglandin E receptor EP2 Subtype." Journal of Biological Chemistry.268. 7759-7762 (1993)
• [Publications] Negishi,M.,et al.: "Two isoforms of prostaglandin E receptor EP3 subtype;different C-terminal domains determine sensitivity to agonist-induced desensitization." Journal of Biological Chemistry.268. 9517-9521 (1993)
• [Publications] Namba,T.,et al.: "Alterative splicing of C-terminal tail of prostaglandin E receptor subtype EP3 determines G-protein specificity" Nature.365. 166-170 (1993)
• [Publications] Ushikubi,F.,et al.: "Thromboxane A2 receptor is highly expressed in immature T cells of mouse thymus and mediates DNA fragmentation." J.Exp.Med.178. 1825-1830 (1993)
• [Publications] Nusing,R.M.,et al.: "Characterization and chromosomal mapping of the human thromboxane A2 receptor gene." Journal of Biological Chemistry.268. 25253-25259 (1993)
• [Publications] Watabe,A.,et al.: "Cloning and expression of cDNA for a EP1 subtype of prostaglandin E receptor." Journal of Biological Chemistry.268. 20175-20178 (1993)
• [Publications] Hashii,M.他: "Bradykinin-induced cytosolic Ca^<2+> oscillations and inositol tetrakisphosphate-induced Ca^<2+> influx in voltage-clamped ras-transformed NIH/3T3 fibroblasts." J.Biol.Chem.268. 19403-19410 (1993)
• [Publications] Abe,H.他: "Immunohistochemical demonstration of [D-Ala2]deltorphin I in amacrine cells of rat retina." Peptides. (印刷中).
• [Publications] Toda,N.他: "Impairment by damage of the pterygopalatine ganglion of nitroxidergic vasodilator nerve function in canine cerebral and retinal arteries." Circ.Res.72. 206-213 (1993)
• [Publications] Ding,W.G.他: "Distribution of taurine-like immunoreactivity in the mouse liver during ontogeny and after carbon tetrachloride or phenobarbital intoxication." Histochem.J.25. 376-383 (1993)
• [Publications] Tooyama,I.他: "Loss of basic fibroblast growth factor in substantia nigra neurons in parkinson's disease." Neurology. 43. 372-376 (1993)
• [Publications] Nakayasu,H.他: "Immunoaffinity purification and characterization of g-aminobutyric acid(GABA)B receptor from bovine cerebral cortex." J.Biol.Chem.268. 8658-8664 (1993)
• [Publications] Nakao,S.-H.他: "High-dose ketamine does not induce c-Fos protein expression in rat hippocampus." Neurosci.Lett.,. 151. 33-36 (1993)
• [Publications] Uemura,S.他: "Mossy fiber sprouting in amygdala and perforant path kindled rats." Jap.J.Psych.Neurol.47. 385-386 (1993)
• [Publications] Snow,B.J.他: "Human positron emission tomographic [18F]fluorodopa studies correlate with dopamine cell counts and levels." Ann.Neurol.34. 324-330 (1993)
• [Publications] Tooyama,I.他: "Immunohistochemical localization of [D-Ala2]deltorphin I in adult rat brain." Proc.Natl.Acad.Sci.U.S.A.90. 9635-9639 (1993)
• [Publications] Nonaka,T.他: "The capacity of central and peripheral catecholaminergic neurons to innervate the peripheral organ and cerebral cortex of the rat." Cell.Tissue Res.273. 525-531 (1993)
• [Publications] Yasuhara,O.他: "Expression of cystatin C in rat,monkey and human brains." Brain Res.628. 85-92 (1993)
• [Publications] Matsuyama,K.他: "Termination mode and braching patterns of reticuloreticular and reticulospinal fibers of the nucleus retularis pontis oralis in the cat." Neurosci.Res.17. 9-21 (1993)
• [Publications] 熊澤孝朗: "新医科学大系第7巻「刺激の受容と生体運動」" 中山書店(印刷中),
• [Publications] Kumazawa,T.: "Proceedings of the 7th World Congress on Pain." IASP Publication(Elsevier)(印刷中),
• [Publications] Caulfield,M.P.et al: "Prog.Brain Research 98" Postsynaptic actions of actylcholine:the coupling of muscarinic receptor subtypes to neuronal ion channels., 293-301 (1993)
• [Publications] Brown,D.A.et al: "Ann.New York Acad.Sci.707" Coupling of muscarinic receptor subtypes to ion channels:Experiments on neuroblastoma hybrid cells., 237-258 (1993)
• [Publications] 堀哲郎,他: "「生気象学の辞典」日本生気象学会編 分担執筆 体温調節の中枢機序pp.194-195 体温調節と免疫機能pp.198-199" 朝倉書店, 447 (1992)
• [Publications] 堀哲郎,他: "「神経内分泌免疫学」(井村裕天,堀哲郎,村松繁編)分担執筆pp.10-16,90-94,185-197,197-205,101-110,171-184." 朝倉書店, 312 (1993)
• [Publications] 堀哲郎: "最新内科学体系 第12巻 間脳・下垂体疾患(猿田享男,長滝重信,松倉茂編) 分担執筆 体温pp.66-72" 中山書店, 456 (1993)
• [Publications] 片渕俊彦,他: "「サイトカインと疾患」平野俊夫編 分担執筆 神経内分泌系とサイトカイン pp56-68" 羊土社, 151 (1993)
• [Publications] 堀哲郎: "新編感覚・知覚心理学ハンドブック(大山正,今井省吾,和気典二編)分担執筆 温度感覚" 誠信書房, 1739(1249-1261) (1994)
• [Publications] Noda,M.et al.: "Ann.New York Acad.Sci.707" Endothelin induces phosphoinositide metabolites-dependent cellular responses in NG108-15 hybrid cells., 482-485 (1993)