酸敏感离子通道(ASICs)是一类可以直接被组织酸化(即质子，H+)激活的离子通道，它影响从学习记忆到细胞损失等多种生理和病理过程。继2005年在Neuron杂志发表ASICs是介导缺血诱导海马皮层神经细胞损伤的重要分子后，中科院神经所徐天乐研究员领导的课题组，近日揭示了ASICs参与慢性痛的诱发和维持的机制。此项研究成果于10月10日在线发表于Journal of Neuroscience杂志。
病理性慢性痛是一种与炎症、神经损伤、糖尿病和肿瘤等疾患相关的不愉快主观感觉和情绪体验，严重影响人类健康和生活质量。作为现代临床医学的主要难题之一，慢性痛诱发和维持的机制至今不清。早在2004年，徐天乐课题组就发现了痛觉传输中枢第一站——脊髓背角，特异性表达一种通透Na＋和Ca2＋的同聚体ASIC1a离子通道(伍龙军等, J Biol Chem)。经过随后三年多潜心研究，由段波、伍龙军等人组成的研究小组发现：在一种慢性痛模型(外周炎症)中，脊髓背角神经元中ASIC1a的蛋白表达量明显增加。行为学实验表明，在这种慢性痛模型中，抑制脊髓背角ASIC1a通道或降低其蛋白表达，都产生明显镇痛效果；而这一系列处理，却不影响对照组正常动物的生理性痛反应。通过与第四军医大学唐都医院陈军教授课题组合作， 研究人员进一步发现ASIC1a通道之所以参与病理性痛觉传递，是因为过高表达的ASIC1a通道增加了整体动物脊髓背角神经元的兴奋性和可塑性，最终导致中枢神经系统敏感化和慢性痛。上述研究结果揭示了生物体内痛觉诱发和维持的一种新机制，并且提示脊髓背角的ASIC1a通道可能成为研究镇痛药物的新靶点。
原始出处:
The Journal of Neuroscience, October 10, 2007, 27(41):11139-11148; doi:10.1523/JNEUROSCI.3364-07.2007
Neurobiology of Disease
Upregulation of Acid-Sensing Ion Channel ASIC1a in Spinal Dorsal Horn Neurons Contributes to Inflammatory Pain Hypersensitivity
Bo Duan,1,2 * Long-Jun Wu,1 * Yao-Qing Yu,3 Yu Ding,1 Liang Jing,1,4 Lin Xu,4 Jun Chen,3 and Tian-Le Xu1,2
1Institute of Neuroscience and State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China, 2School of Life Sciences, University of Science and Technology of China, Hefei 230027, China, 3Institute for Biomedical Sciences of Pain and Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China, and 4Laboratory of Learning and Memory, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
Correspondence should be addressed to either of the following: Dr. Tian-Le Xu, Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China, Email: tlxu@ion.ac.cn ; or Dr. Jun Chen, Institute for Biomedical Sciences of Pain and Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China, Email: junchen@fmmu.edu.cn
Development of chronic pain involves alterations in peripheral nociceptors as well as elevated neuronal activity in multiple regions of the CNS. Previous pharmacological and behavioral studies suggest that peripheral acid-sensing ion channels (ASICs) contribute to pain sensation, and the expression of ASIC subunits is elevated in the rat spinal dorsal horn (SDH) in an inflammatory pain model. However, the cellular distribution and the functional consequence of increased ASIC subunit expression in the SDH remain unclear. Here, we identify the Ca2+-permeable, homomeric ASIC1a channels as the predominant ASICs in rat SDH neurons and downregulation of ASIC1a by local rat spinal infusion with specific inhibitors or antisense oligonucleotides markedly attenuated complete Freund's adjuvant (CFA)-induced thermal and mechanical hypersensitivity. Moreover, in vivo electrophysiological recording showed that the elevated ASIC1a activity is required for two forms of central sensitization: C-fiber-induced "wind-up" and CFA-induced hypersensitivity of SDH nociceptive neurons. Together, our results reveal that increased ASIC activity in SDH neurons promotes pain by central sensitization. Specific blockade of Ca2+-permeable ASIC1a channels thus may have antinociceptive effect by reducing or preventing the development of central sensitization induced by inflammation.
Key words: acid-sensing ion channel; spinal dorsal horn; calcium; sensitization; plasticity; inflammation; chronic pain
