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Activation of acid-sensing ion channel 3 by lysophosphatidylcholine 16:0 mediates psychological stress-induced fibromyalgia-like pain
  1. Chih-Hsien Hung1,2,3,
  2. Cheng-Han Lee2,
  3. Ming-Hsien Tsai4,
  4. Chu-Huang Chen5,6,7,
  5. Hsiu-Fen Lin1,
  6. Chung-Yao Hsu1,
  7. Chiou-Lian Lai1,3,
  8. Chih-Cheng Chen2,3,8
  1. 1Department of Neurology, Kaohsiung Medical University Hospital; Kaohsiung Medical University, Kaohsiung, Taiwan
  2. 2Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  3. 3PhD program in Translational Medicine, Kaohsiung Medical University and Academia Sinica, Kaohsiung / Taipei, Taiwan
  4. 4Department of Child Care, National Pingtung University of Science and Technology, Pingtung, Taiwan
  5. 5Vascular and Medicinal Research, Texas Heart Institute, Houston, Texas, USA
  6. 6Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
  7. 7Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
  8. 8Taiwan Mouse Clinic, National Comprehensive Mouse Phenotyping and Drug Testing Center, Academia Sinica, Taipei, Taiwan
  1. Correspondence to Professor Chih-Cheng Chen, Institute of Biomedical Sciences Academia Sinica, Taipei 115, Taiwan; chih{at}ibms.sinica.edu.tw; Professor Chiou-Lian Lai; cllai{at}kmu.edu.tw

Abstract

Objectives Fibromyalgia is commonly considered a stress-related chronic pain disorder, and daily stressors are known triggers. However, the relation between stress and pain development remains poorly defined by clinical approaches. Also, the aetiology remains largely unknown.

Methods We used a newly developed mouse model and lipidomic approaches to probe the causation and explore the biological plausibility for how perceived stress translates into chronic non-inflammatory pain. Clinical and lipidomic investigations of fibromyalgia were conducted for human validation.

Results Using non-painful sound stimuli as psychological stressors, we demonstrated that mice developed long-lasting non-inflammatory hyperalgesia after repeated and intermittent sound stress exposure. Elevated serum malondialdehyde level in stressed mice indicated excessive oxidative stress and lipid oxidative damage. Lipidomics revealed upregulation of lysophosphatidylcholine 16:0 (LPC16:0), a product of lipid oxidisation, in stressed mice. Intramuscular LPC16:0 injection triggered nociceptive responses and a hyperalgesic priming-like effect that caused long-lasting hypersensitivity. Pharmacological or genetic inhibition of acid-sensing ion channel 3 impeded the development of LPC16:0-induced chronic hyperalgesia. Darapladib and antioxidants could effectively alleviate the stress-induced hyperalgesia by inhibiting LPC16:0 synthesis. Clinical investigations showed that excessive oxidative stress and LPC16:0 expression also exist in patients with fibromyalgia. Moreover, LPC16:0 expression was correlated with pain symptoms in patients with high oxidative stress and disease severity.

Conclusions Our study provides experimental evidence for the causal effect of psychological stressors on chronic pain development. The findings identify a possible pathophysiological mechanism of stress-induced chronic non-inflammatory pain at molecular, behavioural and clinical levels that might indicate a new therapeutic approach for fibromyalgia.

  • ASIC3
  • fibromyalgia
  • lysophosphatidylcholine
  • oxidative stress
  • pain
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Footnotes

  • Handling editor Josef S Smolen

  • Contributors C-HH and C-CC designed research and funding acquisition; C-HL contributed to methodology and resources of gene modified animals; M-HT and C-HC contributed to methodology and data of lipidomic analysis; H-FL, C-YH and C-LL contributed to supervision and critical revision of manuscript.

  • Funding This work was supported by intramural funding from the Institute of Biomedical Sciences, Academia Sinica and grants from the Ministry of Science and Technology, Taiwan (MOST106-2314-037-018 to C-HH; MOST105-2320-B-001-018-MY3, MOST108-2319-B-001-003, MOST108-2321-B-001-005, MOST108-2321-B-001-028-MY2 to C-CC).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request.

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