| 摘要: | 芍藥是一傳統上常用於活血、解痙、去瘀、止痛的藥物，而芍藥■為其主要成分，且媒介此藥理活性。由我們實驗室之前的研究中，發現芍藥能抑制福馬林、醋酸及熱板所致之疼痛反應。 近年來，對NMDA接受器的相關研究中，發現其與痛覺傳導，中樞神經興奮訊息，有相當密切的關係，由於福馬林試驗可能與NMDA接受體有關，而芍藥■對福馬林試驗有抑制作用，為了探討芍藥■與NMDA接受器之關係，所以首先我們利用鎮痛實驗來驗證其二者之間的關係。結果發現，芍藥■表現出明顯之抑制疼痛的效果，併用NMDA接受器拮抗劑之後，止痛的效果更加顯著，且有劑量依存性的表現。另外，對於藥物引起的中樞興奮性行為之影響，我們利用glutamate接受器作用劑，在小鼠身上會引發出抓與咬的行為，芍藥■在此部分的實驗也表現出明顯的抑制效果，併用上glutamate接受器拮抗劑，如MK-801、NBQX、AP5，則有顯著加強的效果；特別是對NMDA所引起的反應，抑制效果最好，且有劑量依存性的表現。 利用反序寡去氧核■序列（NR1， 2A， 2B， 2C），來探討芍藥■對於藥物所引發的中樞興奮性行為的抑制作用。此部分結果發現，只有對高劑量嗎啡的類痙攣反應的起始時間及反應次數上，出現了較明顯的抑制效果；無論NR1，2A，2B或2C而且併用芍藥■（48，96，240 ■g）之後抑制作用更加明顯，且有劑量依存性。NR1，2A，2B，2C作用對NMDA所致之中樞興奮性反應，在第一天之抑制作用不明顯，而於第3、7天，則顯現有抑制作用，併用芍藥■後亦見顯著抑制效果。此外，從電生理方面發現，芍藥■會抑制大鼠下視丘腦薄片中由NMDA所誘發的興奮電位。從西方點墨法中，更進一步得到證實，連續1、3、7天投與反序寡去氧核■序列（NR2B）之後，觀察鼷鼠腦部的NMDA接受器之蛋白質表現，結果發現NMDA接受器之蛋白質會隨時間漸進性而降低表現，而併用芍藥■後呈現劑量依存性。在免疫化學染色的結果，也觀察出NMDA接受器之分佈數量會隨時間漸進性而降低表現，併用芍藥■後，亦有劑量依存性的抑制作用。 從以上結果，我們得到一個結論，芍藥■對於藥物引起的中樞興奮性行為之抑制性保護作用的機轉，可能是與抑制NMDA接受體之活性有密切的關係。; Paeoniae radix has been used to relieve spasmodic abdominal pain. Paeoniflorin, a major component from Paeonia lactifloria, has several pharmacological effects including antiallergic, antinociceptive, antispasmodic and anti-inflammatory actions. In our previous studies, we found that paeoniflorin had antinociceptive effect on both formalin test and writhing response. In this study, we tried to investigate the effect of paeoniflorin on drug-induced central excitatory behavior. Effect of paeoniflorin (48, 96, 240 ?g / 5?l i.c.v.) alone or coadministered with glutamate receptor antagonists (MK-801, AP5, NBQX i.t.) on intrathecal administration of different drug-induced central excitatory behavior were studied. Drugs (NMDA, AMPA, glutamate, strychnine and substance P etc.) agonist intrathecally administered evoked scratching and biting behavior, whereas, glutamate receptor antagonists attenuated scratching and biting behavior induced by glutamate receptor agonists. The effect of glutamate receptor antagonists on drug-induced central excitatory behavior was potentiated by co-administration of paeoniflorin. The results revealed the effect of glutamate receptor antagonists was potentiated by paeoniflorin. To test the involvement of paeoniflorin in the drugs induced excitatory behaviors on NMDA receptor, the effects of an antisense oligodeoxynucleotide against (NR1, 2A, 2B, and 2C) on the NMDA and high dose morphine induced excitatory behaviors were studied. The results of intrathecal treatment once daily antisense oligodeoxy-nucleotides significantly attenuated high dose morphine induced excitatory behavior on day1, on day 3 and 7, significantly attenuated NMDA induced excitatory behavior. The effect of antisense oligodeoxynucleotide on drug-induced central excitatory behavior was potentiated by co-administration of paeoniflorin. Furthermore, from the results of immunohistochemical detection of NMDA receptor in mice brain cortex. These immunohistochemistry and western blot results were consistent with our conclusions that the behavioral effects of the NMDA receptor antisense oligodeoxynucleotide did result from the downregulation of the NMDA receptors by antisense oligodeoxy-nucleotide. From our results, it was suggested that the effect of paeoniflorin on drug-induced central excitatory behavior might via the inactivation of NMDA receptor. |
