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The Journal of Neuroscience, October 10, 2007, 27(41):11139-11148; doi:10.1523/JNEUROSCI.3364-07.2007

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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 Xu^1,2

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{at}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{at}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

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Received March 19, 2007; revised Aug. 20, 2007; accepted Aug. 24, 2007.

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{at}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{at}fmmu.edu.cn

This article has been cited by other articles:

				A. Baron, N. Voilley, M. Lazdunski, and E. Lingueglia Acid Sensing Ion Channels in Dorsal Spinal Cord Neurons J. Neurosci., February 6, 2008; 28(6): 1498 - 1508. [Abstract] [Full Text] [PDF]

				T. W. Sherwood and C. C. Askwith Endogenous Arginine-Phenylalanine-Amide-related Peptides Alter Steady-state Desensitization of ASIC1a J. Biol. Chem., January 25, 2008; 283(4): 1818 - 1830. [Abstract] [Full Text] [PDF]

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