抑制OGR1表現可減緩慢性神經性疼痛藉由減少顆粒性白血球數及非IB4神經元之鈣訊號;OGR1 knockdown reduces granulocyte number and calcium signals of IB4-negative neurons to relieve chronic neuropathic pain

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题名:	抑制OGR1表現可減緩慢性神經性疼痛藉由減少顆粒性白血球數及非IB4神經元之鈣訊號;OGR1 knockdown reduces granulocyte number and calcium signals of IB4-negative neurons to relieve chronic neuropathic pain
作者:	秦茵;Chin, Yin
贡献者:	生命科學系
关键词:	疼痛;G蛋白耦合受體;坐骨神經;痛覺過敏;神經性疼痛
日期:	2019-08-26
上传时间:	2019-09-03 14:33:46 (UTC+8)
出版者:	國立中央大學
摘要:	神經病變性疼痛是由中樞或周邊神經系統病變或受損引起的疼痛，症狀包含自發性疼痛、感覺異常和痛覺過敏，並且還會嚴重干擾病人的生活品質。神經損傷往往伴隨著發炎反應。當發炎發生時，受損部位會釋放細胞因子並誘導免疫細胞聚集。此外，受損部位的組織酸化也在神經損傷中有著重要作用。卵巢癌G 蛋白偶聯受體1（OGR1）是一種在pH6.8 環境下會被活化並且表達於小直徑背根神經節（DRG）神經元上的酸敏感受體，除此之外還有表達在巨噬細胞和T 淋巴細胞等免疫細胞上。細胞因子增加免疫細胞中的OGR1 表達以調節免疫細胞的功能。但是，目前尚不清楚OGR1 在神經性疼痛中的作用為了解決這些問題，我使用坐骨神經慢性壓迫性損傷模型（Chronic constriction injury, CCI），並以shRNA 抑制周邊神經元上OGR1 表達以研究其影響。靜默OGR1 基因表達改善CCI 誘導的機械痛覺過敏。在DRG 神經元中也發現抑制OGR1 基因表達可以在手術後第4 周抑制其鈣訊號。這些結果顯示OGR1 可以調節細胞內神經元中的鈣信號反轉CCI 誘導的機械痛覺過敏。;Neuropathic pain is one of the chronic pain that causes severe disturbance to quality of life. Inflammation accompanied with the nerve injury is associated with induction of neuropathic pain. While inflammation happened, cytokines release and induce immune cells recruitment. Furthermore, the local tissue acidosis accompanied with the nerve injury also plays an important role in neuropathic pain. Ovarian Cancer G Protein-Coupled Receptor 1 (OGR1), a proton-sensing GPCR fully activated at pH6.8 environment is expressed in small-diameter dorsal root ganglion (DRG) neurons, macrophages and lymphocytes. Cytokines increase OGR1 expression in immune cells to regulate the function of immune cells. However, it remains unclear which role OGR1 plays in neuropathic pain. To address these questions, used shRNA to knockdown OGR1 gene expression in peripheral afferents before chronic constriction injury (CCI) of the sciatic nerve. Knockdown of OGR1 gene expression reversed CCI-induced mechanical hyperalgesia from 4 weeks to 14weeks post CCI surgery. Intracellular calcium signals recorded in DRG neurons were upregulated post CCI surgery, and further increased at least 4w. Suppression of OGR1 gene expression inhibited calcium signals at 4w after CCI, maining in IB4(-) neurons. Accordingly, these results suggested that OGR1 may regulate intracellular calcium signals in neuron to reverse CCI-induced mechanical hyperalgesia.
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