Peripheral ASIC3 activation involves in the late phase of CCI-induced mechanical allodynia by switching CGRP-positive population from small to large diameter neurons

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Title:	Peripheral ASIC3 activation involves in the late phase of CCI-induced mechanical allodynia by switching CGRP-positive population from small to large diameter neurons
Authors:	龔家騏;Kung, Chia-Chi
Contributors:	生命科學系
Keywords:	酸敏性離子通道;神經慢性壓迫性損傷;ASIC3;CGRP;neuropathic pain
Date:	2021-01-11
Issue Date:	2021-03-18 16:50:29 (UTC+8)
Publisher:	國立中央大學
Abstract:	ASIC酸敏性離子通道是電壓閘門低感度控制型的陽離子通道，當細胞外氫離子濃度上升時會開啟。ASIC3第三型酸敏性離子通道大量存在背根神經節中。神經受傷會導致背根神經節興奮增加。經由鈣通道流入的鈣離子對疼痛的產生有關。有研究提出，隨著H+濃度的上升會催化ASIC3 通道對鈣離子的開啟。在我們實驗室先前的數據中顯示，ASIC3基因剃除小鼠在神經慢性壓迫性損傷(Chronic constriction injury , CCI)術後4至8周有機械痛覺過敏緩解的情形。因此，我試圖瞭解在神經慢性壓迫性損傷(CCI)小鼠背根神經節中，ASIC3的表現量、背根神經節神經元表現型的轉換、鈣離子分佈和神經痛之間的關係。結果顯示，在神經慢性壓迫性損傷術後，小鼠產生單側機械性和熱覺痛覺過敏、背根神經節中ASIC3表現量增加、背根神經節中小神經元損失增加及神經元鈣離子濃度和具CGRP陽性的神經元增加。在注射第三型酸敏性離子通道的阻斷劑APETx2後，背根神經節中神經元鈣濃度、具CGRP陽性的神經元、背根神經節中ASIC3表現量以及神經痛行為上痛覺過敏的情形都下降。因此，基於上述發現，我認為在神經痛發展的後期，背根神經節中ASIC3參與了具CGRP陽性表現型神經元的轉換，神經元中鈣離子濃度的調控及神經痛的表現有關。 ;ASICs, acid-sensing ion channels, are distributed between the central nervous system and peripheral nervous system specifically, where ASIC3 displays the highest expression than other subunits in DRG neurons. ASICs are voltage-insensitive cationic channels that are activated by the reduction of extracellular pH. ASIC3 channels has been proposed to be opened by catalyzing the relief of Ca2+ blockade as the H+ concentration rises. Calcium is an intracellular messenger and calcium signaling play a key role in neuronal gene expression. Ca2+ currents within the DRG participate in the development of neuropathic pain. Our previous data showed that mechanical hyperalgesia in ASIC3 knockout mice was attenuated gradually during postoperative 4 to 8 weeks. Accordingly, I tried to know the relationship among ASIC3 expression, neuron phenotype switching and calcium distribution in DRGs of Chronic constriction injury (CCI) mice. Results revealed that unilateral mechanical and thermal hyperalgesia, upregulation of ASIC3, more small neuron loss, higher intracellular calcium concentration and switching CGRP positive neuron develop in mice of CCI model. After injection of APETx2, a specific ASIC3 blocker, significant reduction of intracellular calcium concentration, decrease in ASIC3 expression and CGRP expression in neurons are noted which is associated with attenuated behavioral hyperalgesia. Therefore, based on these findings, I infer that ASIC3 involves in neurons CGRP phenotype switching and neuron calcium modulation and neuropathic pain development.
Appears in Collections:	[生命科學研究所 ] 博碩士論文

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