1999 Fiscal Year Final Research Report Summary
Basic Research for Development of New Pharmacotherapy for Neurogenic Voiding Dysfunction
| Project/Area Number |
09671598
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Urology
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
KAKIZAKI Hidehiro Hokkaido Univ., Grad. School of Med., Assi. Pro., 医学部・附属病院, 講師 (10241324)
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| Co-Investigator(Kenkyū-buntansha) |
AMEDA Kamane Hokkaido Univ., Grad. School of Med., Inst., 医学部, 助手 (60271657)
SHIBATA Takashi Hokkaido Univ., Grad. School of Med., Inst., 医学部・附属病院, 助手 (50292032)
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| Project Period (FY) |
1997 – 1999
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| Keywords | Neurogenic Voiding Dysfunction / Glutamate Receptor / Serotonin / Micturition Reflex |
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| Research Abstract |
Histological studies using in situ hybridization combined with retrograde Fast Blue labeling revealed that expressions of subunit mRNAs of both AMPA and NMDA receptor channels are distinct between parasympathetic preganglionic neurons (PGNs) and somatomotor neurons in the ventral horn (Onuf nucleus), indicating different functional properties in regard to AMPA and NMDA glutamate receptors between PGNs and Onuf nucleus.
Electrophysiological studies in the rat revealed that AMPA and NMDA glutamatergic synaptic mechanisms play a key role in the spinal processing of afferent input from the bladder and that these mechanisms function synergistically in the ascending limb of the spinobulbospinal micturition reflex pathway. Another set of physiological studies showed that a selective 5-HTィイD21AィエD2 receptor antagonist inhibited the descending limb but not the ascending limb of the spinobulbospinal micturition reflex pathway via actions on the lumbosacral spinal cord, suggesting a role of 5-HTィイD21AィエD2 receptor in the central neural mechanisms controlling micturition. Regarding the effects of metabotropic glutamate receptor (mGluR) agonist or antagonist, MCPG , an antagonist of mGluR I and II , did not block micturition reflex, while trans-ACPD, an agonist of mGluR II, III, V and I, inhibited micturition reflex if injected intrathecally at lumbosacral spinal cord level but not injected intravenously. The effect of trans-ACPD was mediated at least, by the action on the descending limb of the micturition reflex pathway.
From these data, pharmacotherapy targeting on glutamate receptors and 5-HT (serotonin) receptors within the spinal cord will be a promising modality to manage voiding dysfunction in patients with neurological diseases.
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