酸敏感離子通道(ASICs)是一類可以直接被組織酸化(即質(zhì)子,,H+)激活的離子通道,它影響從學(xué)習(xí)記憶到細(xì)胞損失等多種生理和病理過程,。繼2005年在Neuron雜志發(fā)表ASICs是介導(dǎo)缺血誘導(dǎo)海馬皮層神經(jīng)細(xì)胞損傷的重要分子后,,中科院神經(jīng)所徐天樂研究員領(lǐng)導(dǎo)的課題組,近日揭示了ASICs參與慢性痛的誘發(fā)和維持的機(jī)制,。此項(xiàng)研究成果于10月10日在線發(fā)表于Journal of Neuroscience雜志,。
病理性慢性痛是一種與炎癥、神經(jīng)損傷,、糖尿病和腫瘤等疾患相關(guān)的不愉快主觀感覺和情緒體驗(yàn),,嚴(yán)重影響人類健康和生活質(zhì)量。作為現(xiàn)代臨床醫(yī)學(xué)的主要難題之一,,慢性痛誘發(fā)和維持的機(jī)制至今不清,。早在2004年,徐天樂課題組就發(fā)現(xiàn)了痛覺傳輸中樞第一站——脊髓背角,,特異性表達(dá)一種通透Na+和Ca2+的同聚體ASIC1a離子通道(伍龍軍等, J Biol Chem),。經(jīng)過隨后三年多潛心研究,,由段波、伍龍軍等人組成的研究小組發(fā)現(xiàn):在一種慢性痛模型(外周炎癥)中,,脊髓背角神經(jīng)元中ASIC1a的蛋白表達(dá)量明顯增加,。行為學(xué)實(shí)驗(yàn)表明,在這種慢性痛模型中,,抑制脊髓背角ASIC1a通道或降低其蛋白表達(dá),,都產(chǎn)生明顯鎮(zhèn)痛效果;而這一系列處理,,卻不影響對照組正常動物的生理性痛反應(yīng),。通過與第四軍醫(yī)大學(xué)唐都醫(yī)院陳軍教授課題組合作, 研究人員進(jìn)一步發(fā)現(xiàn)ASIC1a通道之所以參與病理性痛覺傳遞,,是因?yàn)檫^高表達(dá)的ASIC1a通道增加了整體動物脊髓背角神經(jīng)元的興奮性和可塑性,,最終導(dǎo)致中樞神經(jīng)系統(tǒng)敏感化和慢性痛。上述研究結(jié)果揭示了生物體內(nèi)痛覺誘發(fā)和維持的一種新機(jī)制,,并且提示脊髓背角的ASIC1a通道可能成為研究鎮(zhèn)痛藥物的新靶點(diǎn)。
原始出處:
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: [email protected] ; 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: [email protected]
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