酸敏性離子通道在實驗性自體免疫腦脊髓炎所引起之神經痛的角色

Roles of Acid-Sensing Ion Channels in neuropathic pain induced by experimental autoimmune encephalomyelitis

王意清(I-Ching Wang)

指導教授 ： 陳志成

國立臺灣大學/生命科學院/生命科學系/碩士(2015年)

https://doi.org/10.6342/NTU.2015.11177

摘要

神經痛是多發性硬化症的主要症狀之一，然而其成因目前尚未清楚。由於發病過程中的發炎反應會引起組織局部酸化，進而活化與疼痛相關的酸敏性離子通道。所以我假設酸敏性離子通道可能會參與在多發性硬化症的疼痛機制，並利用其動物模式「實驗性自體免疫腦脊髓炎」(EAE)來評估在四種不同酸敏性離子通道基因剔除老鼠中，各自的病程和疼痛反應。結果顯示所有老鼠都會發病，而且在後期的疼痛反應都有增加。其中第一型酸敏性離子通道基因剔除老鼠在發病和疼痛反應都有比較減緩，而第二型酸敏性離子通道剔除老鼠則只有發病程度減緩。為了探討周邊神經在EAE中所受到的影響中所受到的影響，我將百日咳毒素(Pertusiss toxin)拿掉，使得活化的免疫細胞留在周邊，並將此方法命名為EAEnp。這些老鼠和EAE有相似程度的疼痛，但是卻沒有明顯的病兆。而進一步脊髓的染色顯示出EAE老鼠有大量免疫細胞的侵入，以及髓鞘細胞的損傷。
我接著以活化轉錄因子3 (ATF3)作為神經受損既暨神經性疼痛的分子標記，發現EAE和EAEnp老鼠的部分周邊神經都有受損。進一步分類受損的神經細胞後，發現這些受傷的神經細胞大多數為有髓鞘的以及非泌肽類神經元。這些結果顯示周邊神經可能有參與在EAE的疼痛機制中。最後，我們測試了實驗室研發中的止痛藥T1-11，發現不僅可以緩和EAE老鼠的疼痛，而且止痛的機制需要第三型酸敏性離子通道的參與。

關鍵字

多發性硬化症 ； 實驗性自體免疫腦脊髓炎 ； 神經痛 ； 酸敏性離子通道 ； 活化轉錄因子3 ； T1-11

並列摘要

Neuropathic pain is one of the major symptoms in Multiple Sclerosis (MS), but the underlying mechanisms remain a mystery. Since multiple sclerosis is reported to show tissue acidosis, I hypothesized that acid-sensing ion channels (ASICs), which are involved in acid-induced pain, may play a role in pain development in MS. I utilized experimental autoimmune encephalomyelitis (EAE), a well-established MS rodent model, to assess clinical deficits, mechanical hyperalgeisa, and pathological alterations in four different ASIC subtypes knockout mice. All of the mice showed clinical deficits and mechanical hypersensitivity after EAE induction. However, Asic1a-/- EAE mice showed ameliorated disease progression and mechanical hyperalgesia. Interestingly, Asic2-/- EAE mice showed alleviated disease score, but elicited similar levels of pain response as wildtype EAE mice. Furthermore, we removed Pertussis toxin from EAE induction, which named EAEnp, to identify the peripheral contribution to EAE-induced neuropathic pain. These mice showed comparable levels of pain response as EAE mice with little or no clinical signs. Also, pathological studies demonstrated that spinal cord infiltration and demyelination was severe in EAE but not in the EAEnp mice. Nonetheless, some dorsal root ganglion (DRG) neurons are injured in both EAE and EAEnp mice labeled by neuron injury/neuropathic pain marker, ATF3. Further characterization of injured DRG neurons revealed that most of the injury occurred in myelinated neurons as well as non-peptidergic neurons while absent in peptidergic neurons. These results suggested that peripheral sensory nerve might participate in the nociceptive hypersensitivity in EAE. Moreover, a new analgesic drug, T1-11, application indicated that T1-11 effectively modulate EAE-induced mechanical hyperalgesia through ASIC3-dependent mechanism.

並列關鍵字

multiple sclerosis ； EAE ； neuropathic pain ； Asics ； ATF3 ； T1-11

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