実験的触覚過敏の調節機構 : N-methyl-D-aspartate 受容体阻害薬と各種受容体作用薬の相互作用による検討

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The spinally delivered NMDA receptor antagonist, MK-801, has an anti-allodynic action, which suggests possible involvement of increased glutamatergic nerve activity in the spinal cord. The present study characterizes the interaction, in relation to spinal glutamate release, between MK-801 and other drugs, including baclofen (Bac), GABA-B receptor agonist, R-PIA, adenosine A, receptor agonist, and morphine (Mor), opioid receptor agonist, in a rat model of GABA-A receptor antagonist, bicuculline (BIC)-induced tactile-allodynia. Male Sprague-Dawley rats were anesthetized with halothane and a PE-10 catheter and a microdialysis probe were implanted into the lumber intrathecal (I.T.) space. Three days later, rats under halothane anesthesia (1.0%) were subjected to two series of studies : 1) establishment of the effect of I.T. drug alone (low and high doses) on touch-evoked agitation (TEA), and 2) interaction of MK-801 with other drugs on the TEA score and on CSF-glutamate level. TEA score was graded as 0 : no response to 3 : strong agitation with vocalization and assessed by summation of the TEA scores for 30min. (10min. intervals). CSF-glutamate level was measured by I.T. microdialysis and HPLC-ECD (high performance liquid chromatography with electrochemical detector). I.T. BIC evoked a reliable tactile-allodynia. 1) Rats given a high dose of MK-801 (3μg), Bac (10nmol), or R-PIA (10nmol) showed significant attenuation of the increased TEA score induced by BIC I.T. injection, whereas it was not affected by Mor (5μg). However, all animals given a low dose of each drug did not show any change in TEA score. 2) Combination of MK-801 (1μg) with either Bac (1nmol) or R-PIA (1nmol) showed considerable attenuation of increased TEA score induced by BIC I.T. injection and abolition of increased CSF-glutamate level (70% at 10min.). But, a combination of MK-801 (1μg) with Mor (1μg) did not affect the TEA score and CSF-glutamate level. Tactile-allodynia is mediated by low threshold mechanoreceptors and is sensitive to NMDA receptor antagonists. Intrathecal GABA-B receptor agonist (Bac) or adenosine A_1 receptor agonist (R-PIA) may act to diminish presynaptic glutamate release at the Aβ terminal, while NMDA receptor antagonist (MK-801) blocks WDR neurons postsynaptically. Failure of the anti-allodynic effect of morphine may be due to no innervation of enkephalinergic neurons to Aβ terminal. These different action sites may account for the powerful synergy observed in the present study. Using the NMDA receptor antagonist in combination with either drug that inhibits presynaptic glutamate release may potentiate the effects and reduce the side effects of each drug.
九州歯科学会の論文
1998-02-25

実験的触覚過敏の調節機構 : N-methyl-D-aspartate 受容体阻害薬と各種受容体作用薬の相互作用による検討

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