Upregulation of acid-sensing ion channel ASIC1a in spinal dorsal horn neurons contributes to inflammatory pain hypersensitivity
Upregulation of acid-sensing ion channel ASIC1a in spinal dorsal horn neurons contributes to inflammatory pain hypersensitivity
复制标题
脊髓背角神经元中酸敏感离子通道 ASIC1a 的上调导致炎性疼痛超敏反应
DOI：
10.1523/jneurosci.3364-07.2007
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发表时间：
2007-10-10
影响因子：
5.3
通讯作者：
Xu, Tian-Le
中科院分区：
文献类型：
--
作者：
Duan, Bo;Wu, Long-Jun;Xu, Tian-Le
慢性疼痛的发展涉及外周伤害感受器的改变以及CNS多个区域中神经元活性的升高。先前的药理学和行为学研究表明，外周酸敏感离子通道（ASIC）有助于疼痛感觉，并且在炎症疼痛模型中，大鼠脊髓背角（SDH）中ASIC亚基的表达升高。然而，SDH中ASIC亚基表达增加的细胞分布和功能后果仍不清楚。在这里，我们确定的Ca 2+渗透，同源ASIC 1a通道作为主要的ASICs在大鼠SDH神经元和下调ASIC 1a的局部大鼠脊髓输注特异性抑制剂或反义寡核苷酸显着衰减完全弗氏佐剂（CFA）诱导的热和机械超敏反应。此外，体内电生理记录表明，升高的ASIC 1a活性是两种形式的中枢敏化所必需的：C-纤维诱导的“发条”和CFA诱导的SDH伤害性神经元的超敏反应。总之，我们的研究结果表明，增加ASIC活性的SDH神经元促进疼痛的中枢敏化。因此，特异性阻断Ca 2+渗透性ASIC 1a通道可能通过减少或阻止炎症诱导的中枢致敏的发展而具有抗伤害性作用。
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.