| Project/Area Number |
59870085
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| Research Category |
Grant-in-Aid for Developmental Scientific Research
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| Allocation Type | Single-year Grants |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Tokyo Medical & Dental University, Faculty of Medicine |
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Principal Investigator |
OTSUKA Masanori Tokyo Medical & Dental Univ., Fac. of Medicine, Professor, 医学部, 教授 (60013801)
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| Co-Investigator(Kenkyū-buntansha) |
藤野 政彦 武田製薬中央研究所, 化学研究所, 所長
YANAGISAWA Mitsuhiko Tokyo Medical & Dental Univ., Fac. of Medicine, Lecturer, 医学部, 講師 (90159252)
FUJINO Masahiko Takeda Chemical Inductries, Ltd., Central Research Div. Inst. of Chemistry, Dire
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| Project Period (FY) |
1984 – 1986
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| Project Status |
Completed (Fiscal Year 1986)
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| Budget Amount *help |
¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1986: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1985: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1984: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | Nociception / substance P / substance P antagonist / non-opioid analgesics / 摘出脊髄-尾標本 / 摘出脊髄-知覚神経標本 / 摘出脊髄-伏在神経-皮フ標本 / 侵害反射電位 / 非麻薬性鎭痛薬 / 侵害反射 / モルフィン / メチオニン / エンケファリン / ダイノルフィン / ナロキソン |
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| Research Abstract |
We have developed three kinds of isolated CNS preparations of newborn rats to assay the effects of substance P (SP) antagonists and to study the physiological roles of neuropeptides in spinal nociception. These preparations are: a) an isolated spinal cord-tail preparation, in which application of capsaicin to the tail induces a nociceptive reflex that can be recorded from lumbar ventral roots; b) an isolated spinal cord-peripheral nerve preparation, in which stimulation of the saphenous nerve induces a Cfiber fiber reflex in the L3 ventral roots; and c) a spinal cord-saphenous nervehind limb skin preparation, in which application of capsaicin to the skin induces a nociceptive reflex in the ventral roots. Specific tachykinin antagonists [D- <Arg^1> , D- <Pro^2> , D- <Trp^(7,9)> , <Leu^(11)> ]SP and [D- <Arg^1> , D- <Trp^(7,9)> , <Leu^(11)> ]SP (Spantide) depressed the nociceptive reflexes observed in these isolated preparations, whereas monosynaptic reflex was not affected by the SP antagonists. These results support the role of SP as a pain transmitter in the spinal cord and suggest the potential usefulness of SP antagonists as analgesics.
SP analogues that contain fluorine were synthesized to improve transportation across the blood-brain-barrier. One of these peptide analogues had satisfactory antagonistic action to SP.
In addition, we found that, 1) the endogenous peptides, galanin and somatostatin, in low concentrations depressed nociceptive reflexes; 2) brainstem stimulation caused a descending inhibition of spinal reflexes in an in vitro preparation; 3) prostaglandins potentiated nociception by directly acting on peripheral afferent terminals in isolated spinal cordtail preparations.
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