臺灣博碩士論文加值系統

先前的研究指出神經傳遞物之一的甘丙胺&;#32957; (Galanin)可利用專一性甘丙胺&;#32957;類型二受器 (Galanin receptor 2, GalR2)調控周邊神經系統的痛覺傳遞；當神經損傷時，受損神經元會藉由神經發炎、神經自發性放電及痛覺相關因子釋放的方式，引起神經病變疼痛 (neuropathic pain)。但是有關正中神經髓鞘退化剝離後GalR2及其受質數量上的變化仍欠缺直接證據，更遑論它對正中神經損傷後續誘發行為、發炎的影響。因此，本實驗利用溶血磷脂醯膽鹼（lysophosphatidylcholine,LPC)引發神經髓鞘剝離損傷脫落，作為探討神經損探討正中神經以LPC處理後，GalR2與神經病變疼痛的關係。
LPC處理後，實驗動物手術側產生神經病變疼痛的行為反應。以細胞免疫化學法標誌後，發現在正常大白鼠的背根神經節中，GalR2免疫反應神經元的數量相當少，且主要為小型神經元；在LPC處理一週後，GalR2免疫反應神經元佔背根神經節的的百分比明顯上升，而且在體型的分布有擴展至中型神經元，且相較於小型神經元在數量上有明顯較多的現象。配合雙重免疫螢光標誌法染色時，發現神經損傷後一週GalR2與辣椒素受器 (VR1)、P2X3、peripherin、NF200、NPY及MMP9等的雙重標誌神經元數目及占背根神經節中的比例都有顯著上升。
鑑於神經病變疼痛成因之一有可能來自於神經末端自發性放電 (sponteous discharge)，本實驗又利用抑制鈉離子通道之局部麻醉劑－利多卡因 (lidocaine)術前處理；結果發現lidocaine術前處理可減緩LPC誘發實驗動物神經病變疼痛程度，並降低神經損傷之背根神經節中GalR2免疫反應神經元數量及百分比上升幅度。配合雙重免疫標誌染色，同時也發現神經損傷後一週GalR2與辣椒素受器 (VR1)、P2X3、peripherin、NF200、NPY及MMP9等的雙重標誌神經元數目及占背根神經節中的百分比也有緩和其上升的幅度。
除此之外，LPC處理一週後楔狀神經節內GalR2免疫反應神經元的數量也會高於正常組別，並因為lidocaine處理而有下降的現象。由結果顯示lidocaine的處理可造成神經過敏痛及痛覺相關化學因子的改變，進一步引發抑制痛覺表現的結果。

Previous studies have shown that Galanin modulated peripheral pain sensation via galanin receptor type 2 (GalR2). Following nerve injury, inflammation, spontaneous discharge and upregulation of pain related factors would involve in neuropathic pain development. To our knowledge, the correlation between median nerve demyelination and GalR2 and its substrate expression levels has not been documented; and yet the effect of GalR2 on medain neuropathic pain is not valid. Thus, using LPC treated median nerve injury model, we investigate the role of GalR2 and its pain corelated factors in the upper limb neuropathic pain.
One week after LPC treatment of median nerve induced mechnical allodynia and thermal hyperalgesia. Immunohistochemistry analysis showed that GalR2-like immunoreactive (-LI) neurons were predominately in small-size DRG neurons of normal rats. However, one week after LPC treatment, GalR2-LI neurons not only increased in its percentage but also distributed in medium- and large-sized neurons. Moreover, to characterize GalR2-LI neurons in the DRG was using immunofluorescence double labeling for NF200, peripherin, pain-related factors including vanilloid receptor subtype 1 (VR1), P2X3, NPY, nNOS, Galanin, or MMP9. We found that the number and percentage of GalR2-LI neurons colocalized with NF200, P2X3, NPY, nNOS, Galanin and MMP9 were increased in the LPC-treated DRG. Furthermore, lidocaine pretreatment attenuated the number of upregulated GalR2-LI neurons in the LPC-treated DRG. Our study also found that one week afterLPC treatment, the number of GalR2-LI neurons in the cuneate nucleus of LPC treated rats was higer than that in the control group. The present results suggest that lidocaine pretreatment relieved the development of neuropathic pain partially pass through reducing GalR2 expression.

中文摘要…………………………………....…………………...................…....i
英文摘要…………………………………....…………………….......................iii
壹、前言…...........……………………………………....................…...….….....1
一、 周邊神經損傷 (peripherinal nerve injury)…..………............……….1
二、 Galanin Receptor 2表現對神經損傷的影響…………............……….3
三、 手術傷害前麻醉 (pre-emptive analgesia)於周邊神經之作用…….….4
四、 背側─內側蹄系路徑與神經病變疼痛之關聯…….…........................4
五、 痛覺相關因子在神經損傷下的表現…….…........................……........5
六、 發炎因子在神經損傷下之表現….........................................……........8
七、 實驗目的…..........................................................................…...............8
貳、實驗材料與方法…................……………………………………….…..9
一、 實驗動物…………………………………………...………................9
二、 正中神經去髓鞘的實驗動物模式……………………………….......9
三、 術前局部麻醉處理…………………........………………….…..........9
四、 動物行為測試………................................……………………….......10
五、 動物犧牲……................................……………………….…..............11
六、 背根神經節抗GalR2免疫組織化學反應...........................................11
七、 背根神經節抗GalR2及痛覺相關蛋白雙重免疫螢光染色...............12
八、 楔狀神經核抗GalR2免疫組織化學反應...........................................14
九、 影像分析……................................……………………...……............15
&;#21442;、結果………………………………………….....................………...….......16
一、 局部麻醉劑術前處理對LPC正中神經損傷的神經病變性疼痛行為的影響...................................................................................................16
二、 局部麻醉劑術前處理對LPC正中神經損傷第六頸髓段背根神經節中Galanin Receptor 2神經元的分布與數量變化的影響..................17
三、 局部麻醉劑術前處理對LPC正中神經損傷第六頸髓段背根神經節中Galanin Receptor 2神經元與peripherin或NF200雙重免疫螢光標記的變化..............................................................................................18
1. NF200神經元於第六頸髓背根神經節中的數量變化.................18
2. GalR2與NF200於第六頸髓背根神經節中雙重免疫螢光標記數量變化...........................................................................................18
3. peripherin於第六頸髓背根神經節中的數量變化........................18
4. GalR2與peripherin於第六頸髓背根神經節中共同表現數量變化...................................................................................................19
四、 局部麻醉劑術前處理對LPC正中神經損傷第六頸髓段背根神經節中Galanin Receptor 2與痛覺相關因子雙重標誌變化......................19
1. GalR2與疼痛相關因子於第六頸髓背根神經節中表現量變化...19
2. GalR2與NPY於第六頸髓背根神經節中表現量.........................20
3. GalR2與nNOS於第六頸髓背根神經節中表現量.......................20
4. GalR2與P2X3於第六頸髓背根神經節中表現量........................21
5. GalR2與VR1於第六頸髓背根神經節中表現量..........................21
6. GalR2與Nav1.3於第六頸髓背根神經節中表現量.....................22
五、 局部麻醉劑術前處理對LPC正中神經損傷第六頸髓段背根神經節中Galanin Receptor 2神經元與MMP9在雙重免疫螢光標記變化...22
1. MMP9神經元於第六頸髓背根神經節中的數量變化..................22
2. GalR2與MMP9於第六頸髓背根神經節中雙重免疫螢光標記數量變化...........................................................................................23
六、 正中神經以不同手術處理後Galanin Receptor 2免疫反應神經元在楔狀神經核中段區域的分佈情形.......................................................23
肆、討論………………………………………………..………........................24
一、 術前給予2%lidocaine對神經病變疼痛行為影響.............................24
二、 神經損傷後GalR2於背根神經節中表現量增加...............................24
三、 術前給予2%lidocaine對GalR2與疼痛相關因子表現量影響.........26
四、 術前給予2%lidocaine對發炎相關因子表現量影響..........................30
伍、參考文獻………………………………………….....…………................32
陸、圖與圖說………………………………….....…………...............………...40

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