Spatio-temporal analysis by optical imaging of neural plasticity mechanism in neuropathic pain.

• Project/Area Number: 15500270
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Kansai Medical University
• Principal Investigator: MATSUMURA Shinji Kansai Medical University, Faculty of Medicine, Instructor, 医学部, 助手 (70276393)
• Co-Investigator(Kenkyū-buntansha): ITO Seiji Kansai Medical University, Faculty of Medicine, Professor, 医学部, 教授 (80201325)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,700,000 (Direct Cost: ¥3,700,000); Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000); Fiscal Year 2003: ¥2,400,000 (Direct Cost: ¥2,400,000)
• Keywords: Allodynia / Spinal cord / Neural plasticity / Optical imagine / Nitric oxide / Intracellular calcium ion / NMDA receptor / Mouse / nNOS受容体

Research Abstract

Neuropathic pain arising from peripheral nerve injury often becomes intractable pain accompanied by tactile pain (allodynia) and hyperalgesia.
After mice had become neuropathic pain induced by L5 spinal nerve transection, the increase in nitric oxide synthase (NOS) activity was observed in the superficial layer of dorsal horn in the spinal cord by NADPH diaphorase histochemistry. Using the nitric oxide (NO) detection dye, we confirmed that NO production increased in the spinal slice prepared from neuropathic mice and that the increase was more prominent in the ipsilateral side to the nerve transection than in the contralateral side. These increases in NOS activity and NO production in neuropathic mice were blocked by pretreatment of oral JTC-801, non peptidergic nociceptin antagonist. Although intraperitoneal injection of the nonselective NOS inhibitor significantly attenuated neuropathic hyperalgesia, inducible NOS-deficient mice showed neuropathic pain after L5 spinal nerve transectio n. These results suggest that nociceptin is involved in the maintenance of neuropathic pain and that the analgesic effect of JTC-801 on neuropathic pain is mediated by inhibition of NO production by neuronal NOS.
Mice lacking the PACAP gene (PACAP^<-/->) did not exhibit neuropathic pain induced by nerve transection, whereas they did retain normal nociceptive responses. Intrathecal administration of NMDA induced mechanical allodynia in wild-type mice, but not in PACAP-/- mice. The NMDA-induced allodynia in PACAP-/- mice was reproduced by simultaneous intrathecal injection of PACAP with NMDA. Concomitant with the increase in PACAP immunoreactivity after nerve injury, NADPH-dependent NOS activity markedly increased in the superficial layer of the spinal cord of wild-type mice. Simultaneous addition of PACAP and NMDA caused translocation of neuronal NOS from the cytosol to the membrane and stimulated NO production in vitro. These results demonstrate that PACAP might promote the functional coupling of neuronal NOS to NMDA receptors for neuropathic pain to occur.

Research Products

• [Journal Article] Involvement of Rho-kinase in inflammatory and neuropathic pain through phosphorylation of myristoylated alanine-rich C-kinase substrate(MARCKS). (2005)
  • Author(s): Tatsumi, S.
  • Journal Title: Neuroscience 131 Pages: 491-498
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Involvement of Rho-kinase in inflammatory and neuropathic pain through phosphorylation of myristoylated alanine-rich c-kinase substrate (MARCKS). (2005)
  • Author(s): Tatsumi, S., Mabuchi, T., Katano, T., Matsumura, S., Abe, T., Hidaka, H., Suzuki, M., Sasaki, Y., Minami, T., Ito, S.
  • Journal Title: Neuroscience 131 Pages: 491-498
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of Rho-kinase in inflammatory and neuropathic pain through phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS). (2005)
  • Author(s): Tatsumi, S.
  • Journal Title: Neuroscience 131 Pages: 491-498
• [Journal Article] Pituitary adenylate cyclase-activating polypeptide is required for the development of spinal sensitization and induction of neuropathic pain. (2004)
  • Author(s): Mabuchi, T.
  • Journal Title: J.Neurosci. 24 Pages: 7283-7291
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Acute and late effects on induction of allodynia by acromelic acid, a mushroom poison related structurally to kainic acid. (2004)
  • Author(s): Minami, T.
  • Journal Title: Br.J.Pharmacol. 142 Pages: 679-688
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Membrane-associated prostaglandin E synthase-I is required for neuropathic pain. (2004)
  • Author(s): Mabuchi, T., Kojima, H., Abe, T., Takagi, K., Sakurai, M., Ohmiya, Y., Uematsu, S., Akira, S., Watanabe, K., Ito, S.
  • Journal Title: NeuroReport 15 Pages: 1395-1398
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Characterization of N-methyl-D-aspartate receptor subunits involved in acute ammonia toxicity. (2004)
  • Author(s): Kitano, T., Matsumura, S., Seki, T., Hikida, T., Sakimura, K., Nagano, T., Mishina, M., Nakanishi, S., Ito, S.
  • Journal Title: Neurochem.Int. 44 Pages: 83-90
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Pituitary adenylate cyclase-activating polypeptide is required for the development of spinal sensitization and induction of neuropathic pain. (2004)
  • Author(s): Mabuchi, T., Shintani, N., Matsumura, S., Okuda-Ashitaka, E., Hashimoto, H., Muratani, T., Minami, T., Baba, A., Ito, S.
  • Journal Title: J.Neurosci. 24 Pages: 7283-7291
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Acute and late effects on induction of allodynia by acromelic acid, a mushroom poison related structurally to kainic acid. (2004)
  • Author(s): Minami, T., Matsumura, S., Nishizawa, M., Sasaguri, Y., Hamanaka, N., Ito, S.
  • Journal Title: Br.J.Pharmacol. 142 Pages: 679-688
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Characterization of N-methyl-D-aspartate receptor subunits involved in acute ammonia toxicity. (2004)
  • Author(s): Kitano, T.
  • Journal Title: Neurochem.Int. 44 Pages: 83-90
• [Journal Article] Characterization of N-methyl-D-aspartate receptor subunits responsible for postoperative pain. (2004)
  • Author(s): Nishimura, W.
  • Journal Title: Eur.J.Pharmacol. 503 Pages: 71-75
• [Journal Article] Membrane-associated prostaglandin E synthase-I is required for neuropathic pain. (2004)
  • Author(s): Mabuchi, T.
  • Journal Title: Neuroreport 15 Pages: 1395-1398
• [Journal Article] Attenuation of neuropathic pain by nociceptin/orphanin FQ antagonist JTC-801 is mediated by inhibition of nitric oxide production. (2003)
  • Author(s): Mabuchi, T.
  • Journal Title: Eur.J.Neurosci. 17 Pages: 1384-1392
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Functional characterization of prostaglandin F_2α receptor in the spinal cord for tactile pain(allodynia). (2003)
  • Author(s): Muratani, T.
  • Journal Title: J.Neurochem. 86 Pages: 374-382
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Functional evidence for interaction between prostaglandin EP3 and k-opioid receptor pathways in tactile pain induced by human immunodeficiency virus type-1(HIV-1) glycoprotein gp120. (2003)
  • Author(s): Minami, T.
  • Journal Title: Neurophamacology 45 Pages: 96-105
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Attenuation of neuropathic pain by nociceptin/orphanin FQ antagonist, JTC-801 is mediated by inhibition of nitric oxide production. (2003)
  • Author(s): Mabuchi, T., Matsumura, S., Okuda-Ashitaka, E., Kitano, T., Kojima, H., Nagano, T., Minami, T., Ito, S.
  • Journal Title: Eur.J.Neurosci. 17 Pages: 1384-1392
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional characterization of prostaglandin F2α receptor in the spinal cord for tactile pain (allodynia). (2003)
  • Author(s): Muratani, T., Nishizawa, M., Matsumura, S., Mabuchi, T., Abe, K., Shimamoto, K., Minami, T., Ito, S.
  • Journal Title: J.Neurochem. 86 Pages: 374-382
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional evidence for interaction between prostaglandin EP3 and κ-opioid receptor pathways in tactile pain induced by human immunodeficiency virus type-1 (HIV-1) glycoprotein gp120. (2003)
  • Author(s): Minami, T., Matsumura, S., Mabuchi, T., Kobayashi, T., Sugimoto, Y., Ushikubi, F., Ichikawa, A., Narumiya, S., Ito S.
  • Journal Title: Neurophamacology 45 Pages: 96-105
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Mabuchi, T.: "Attenuation of neuropathic pain by the nociceptin/orphanin FQ antagonist TC-801 is mediated by inhibition of nitric oxide production."Eur.J.Neurosci.. 17. 1384-1392 (2003)
• [Publications] Muratani, T.: "Functional characterization of prostaglandin F_<2α> receptor in the spinal cord for tactile pain (allodynia)."J.Neurochem.. 86. 374-382 (2003)
• [Publications] Minami, T.: "Functional evidence for interaction between prostaglandin EP3 and κ-opioid receptor pathways in tactile pain induced by human immunodeficiency virus type-1 (HIV-1) glycoprotein gp120."Neurophamacology. 45. 96-105 (2003)
• [Publications] Kitano, T.: "Characterization of N-methyl-D-aspartate receptor subunits involved in acute ammonia toxicity."Neurochem.Int.. 44. 83-90 (2004)
• [Publications] 伊藤 誠二: "痛み-基礎・診断・治療-"朝倉書店. 407 (2003)