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研究生:林校群
研究生(外文):Hsiao-Chun Lin
論文名稱:觸感痛與gabapentin的止痛作用在神經損傷大鼠腦中的活性變化
論文名稱(外文):The brain activity changes of tactile allodynia and the analgesic effect of gabapentin in the neuropathic rats
指導教授:嚴震東嚴震東引用關係
口試委員:孫維仁閔明源徐百川陳建璋曾凱元曾明宗
口試日期:2015-01-29
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:121
中文關鍵詞:觸感痛Gabapentin前額葉皮質前扣帶迴皮質島狀皮質
外文關鍵詞:allodyniagabapentinmedial prefrontal cortexanterior cingulate cortexinsular cortex
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神經病變性疼痛為體感覺系統因疾病或損傷所產生的疼痛,在臨床上不易治療,因對其病理機制的了解仍有限。觸感痛是神經病變性疼痛的主要症狀,特徵為對正常人無痛的觸覺刺激卻會引發病人疼痛。目前對觸感痛的研究著重在周邊感覺神經及脊髓背角的功能性變化,而腦部在觸感痛時扮演的角色仍待了解。Gabapentin (GBP)是臨床上治療神經病變性疼痛的主要藥物,但其在腦中的作用位置還不清楚。本論文使用正子造影及免疫組織化學方法,研究神經損傷大鼠腦部在觸感痛狀態下的功能性變化,及GBP在腦部可能的作用位置。我們將大鼠坐骨神經的分支脛神經及腓總神經結紮後切斷,保留腓腸神經完整。神經損傷大鼠很快發展出自發性疼痛、觸感痛及痛覺過敏等現象。我們比較神經損傷大鼠在觸感痛狀態下腦部的葡萄糖代謝率及神經活化標誌的變化,以及給予GBP止痛後的改變。由正子造影的結果顯示,觸感痛會使神經損傷大鼠腦部的島狀皮質前側、丘腦及小腦的代謝率增加,而給予GBP止痛可回復丘腦及小腦的代謝率,並使前額葉皮質及前扣帶迴皮質代謝率降低。由免疫組織染色的結果顯示,磷酸化細胞外訊息調節激酶(pERK)及神經活化蛋白(c-Fos)在神經損傷大鼠的前額葉皮質、前扣帶迴皮質及島狀皮質前側等邊緣皮質有大量的表現。神經損傷大鼠腦中pERK細胞在前額葉皮質及島狀皮質前側較對照組有顯著增加,而c-Fos細胞則在前額葉皮質較對照組有顯著增加;經由給予GBP止痛後,這些大量表現的細胞顯著的減少。我們更進一步確認在腦中這些表現pERK或c-Fos的細胞是神經元,而非星狀膠細胞。由本研究的結果可知,觸感痛在神經損傷大鼠腦中主要改變了邊緣皮質的細胞活性,而GBP在腦部的作用位置可能就是在抑制邊緣皮質的細胞活性來達成止痛作用。

Neuropathic pain is caused by injury or disease of the somatosensory system. Treating neuropathic pain is difficult because its pathophysiological mechanisms are understood limitedly. Tactile allodynia, the innocuous touch-evoked pain, is one of the major symptoms of neuropathic pain patients. So far the studies of tactile allodynia are focused on the functional alterations in the primary afferents and the spinal dorsal horn neurons, however, the role of brain in the tactile allodynia is still unclear. Gabapentin (GBP) is a first-line analgesic to treat neuropathic pain, but its action sites in the brain remains to be disclosed. In this thesis, we used positron emission tomography (PET) and immunohistochemical methods to investigate the functional alterations in the brain of neuropathic rats under allodynic state, and the action sites of GBP in the brain. We used the spared nerve injury (SNI) model of neuropathic pain. In the SNI model, the tibia and common peroneal nerves of the sciatic nerve were ligated and cut, and leaving the sural nerve intact. The nerve-injured rats developed spontaneous pain, tactile allodynia and thermal hyperalgesia. Then we compared the glucose metabolic rate and neuronal activation markers in the brain of neuropathic rats under allodynic state, and the effect of GBP. The PET results showed glucose metabolic rates increased in the anterior insular cortex (IC), thalamus and cerebellum after nerve-injury, and GBP treatment reversed the increases in the thalamus and cerebellum, and decreased the glucose metabolism in the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). The immunostaining results showed an abundant expression of pERK and c-Fos in the mPFC, ACC and anterior IC. For pERK study, the pERK-positive cells in the neuropathic rats increased significantly in the mPFC and IC than control rats. For c-Fos study, the c-Fos-positive cells in the neuropathic rats increased significantly in the mPFC than control rats. After GBP treatment, the increased expression of pERK and c-Fos decreased significantly. We also demonstrated the pERK- or c-Fos-positive cells were neurons, not the astrocytes. According to our studies, the tactile allodynia affect the neuronal activities in the limbic cortices of neuropathic rats, and the effect of GBP was to suppress the activation of limbic cortices.

論文口試委員會審定書 i
致謝 ii
摘要 iii
Abstract iv
第一章、緒論 1
1.1 研究神經病變性疼痛的重要性 1
1.2 神經病變性疼痛 1
1.3 腦部對疼痛反應的功能性影像研究 11
1.4 疼痛的細胞分子標記 15
1.5 研究目的 16
第二章、神經損傷大鼠的疼痛行為指標與gabapentin的藥效測試 18
2.1 前言 18
2.2 材料與方法 19
2.3 結果 24
2.4 討論 25
第三章、神經損傷大鼠在觸感痛狀態下的腦部葡萄糖代謝率變化與gabapentin止痛的作用位置 29
3.1 前言 29
3.2 材料與方法 30
3.3 結果 36
3.4 討論 39
第四章、神經損傷大鼠在觸感痛狀態下的腦部神經活化標誌的變化與gabapentin的止痛反應 45
4.1 前言 45
4.2 材料與方法 46
4.3 結果 52
4.4 討論 55
第五章、綜合討論與結論 60
參考文獻 65
附表 81
附圖 85

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