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Roles of ASIC3, TRPV1, and NaV1.8 in the transition from acute to chronic pain in a mouse model of fibromyalgia

Wei-Nan Chen12, Cheng-Han Lee2, Shing-Hong Lin12, Chia-Wen Wong2, Wei-Hsin Sun3, John N Wood4 and Chih-Cheng Chen125*

Author Affiliations

1 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan

2 Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Taipei 115, Taiwan

3 Department of Life Sciences, National Central University, Jhongli 32054, Taiwan

4 Wolfson Institute for Biomedical Research, Molecular Nociception Group, University College London, London WC1E 6BT, UK

5 Taiwan Mouse Clinic—National Comprehensive Mouse Phenotyping and Drug Testing Center, Academia Sinica, 128 Academia Road, Section 2, Taipei 115, Taiwan

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Molecular Pain 2014, 10:40  doi:10.1186/1744-8069-10-40

Published: 23 June 2014



Tissue acidosis is effective in causing chronic muscle pain. However, how muscle nociceptors contribute to the transition from acute to chronic pain is largely unknown.


Here we showed that a single intramuscular acid injection induced a priming effect on muscle nociceptors of mice. The primed muscle nociceptors were plastic and permitted the development of long-lasting chronic hyperalgesia induced by a second acid insult. The plastic changes of muscle nociceptors were modality-specific and required the activation of acid-sensing ion channel 3 (ASIC3) or transient receptor potential cation channel V1 (TRPV1). Activation of ASIC3 was associated with increased activity of tetrodotoxin (TTX)-sensitive voltage-gated sodium channels but not protein kinase Cϵ (PKCϵ) in isolectin B4 (IB4)-negative muscle nociceptors. In contrast, increased activity of TTX-resistant voltage-gated sodium channels with ASIC3 or TRPV1 activation in NaV1.8-positive muscle nociceptors was required for the development of chronic hyperalgesia. Accordingly, compared to wild type mice, NaV1.8-null mice showed briefer acid-induced hyperalgesia (5 days vs. >27 days).


ASIC3 activation may manifest a new type of nociceptor priming in IB4-negative muscle nociceptors. The activation of ASIC3 and TRPV1 as well as enhanced NaV1.8 activity are essential for the development of long-lasting hyperalgesia in acid-induced, chronic, widespread muscle pain.

Acidosis; APETx2; Hyperalgesic priming; IB4; PKCϵ