Involvement of ASIC3 and Substance P in Therapeutic Ultrasound-Mediated Analgesia in Mouse Models of Fibromyalgia

Der-Sheng Han; Cheng-Han Lee; Yih-Dar Shieh; Ke-Vin Chang; Shing-Hong Lin; Ya-Cherng Chu; Jaw-Lin Wang; Chih-Cheng Chen

doi:10.1016/j.jpain.2023.04.003

Involvement of ASIC3 and Substance P in Therapeutic Ultrasound-Mediated Analgesia in Mouse Models of Fibromyalgia

J Pain. 2023 Aug;24(8):1493-1505. doi: 10.1016/j.jpain.2023.04.003. Epub 2023 Apr 11.

Authors

Der-Sheng Han¹, Cheng-Han Lee², Yih-Dar Shieh³, Ke-Vin Chang⁴, Shing-Hong Lin², Ya-Cherng Chu⁵, Jaw-Lin Wang⁵, Chih-Cheng Chen⁶

Affiliations

¹ Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Beihu Branch, Taipei, Taiwan; Department of Physical Medicine and Rehabilitation, National Taiwan University College of Medicine, Taipei, Taiwan; Health Science and Wellness Center, National Taiwan University, Taipei, Taiwan.
² Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
³ Department of Physical Medicine and Rehabilitation, National Taiwan University College of Medicine, Taipei, Taiwan.
⁴ Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Beihu Branch, Taipei, Taiwan; Department of Physical Medicine and Rehabilitation, National Taiwan University College of Medicine, Taipei, Taiwan.
⁵ Department of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.
⁶ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Taiwan Mouse Clinic, Biomedical Translational Research Center, Academia Sinica, Taipei, Taiwan; Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan.

PMID: 37054767
DOI: 10.1016/j.jpain.2023.04.003

Abstract

Therapeutic ultrasound (tUS) is widely used in chronic muscle pain control. However, its analgesic molecular mechanism is still not known. Our objective is to reveal the mechanism of the tUS-induced analgesia in mouse models of fibromyalgia. We applied tUS in mice that have developed chronic hyperalgesia induced by intramuscular acidification and determined the tUS frequency at 3 MHz, dosage at 1 W/cm² (measured output as 6.3 mW/cm²) and 100% duty cycle for 3 minutes having the best analgesic effect. Pharmacological and genetic approaches were used to probe the molecular determinants involved in tUS-mediated analgesia. A second mouse model of fibromyalgia induced by intermittent cold stress was further used to validate the mechanism underlying the tUS-mediated analgesia. The tUS-mediated analgesia was abolished by a pretreatment of NK1 receptor antagonist-RP-67580 or knockout of substance P (Tac1^-/-). Besides, the tUS-mediated analgesia was abolished by ASIC3-selective antagonist APETx2 but not TRPV1-selective antagonist capsazepine, suggesting a role for ASIC3. Moreover, the tUS-mediated analgesia was attenuated by ASIC3-selective nonsteroid anti-inflammation drugs (NSAIDs)-aspirin and diclofenac but not by ASIC1a-selective ibuprofen. We next validated the antinociceptive role of substance P signaling in the model induced by intermittent cold stress, in which tUS-mediated analgesia was abolished in mice lacking substance P, NK1R, Asic1a, Asic2b, or Asic3 gene. tUS treatment could activate ASIC3-containing channels in muscle afferents to release substance P intramuscularly and exert an analgesic effect in mouse models of fibromyalgia. NSAIDs should be cautiously used or avoided in the tUS treatment. PERSPECTIVE: Therapeutic ultrasound showed analgesic effects against chronic mechanical hyperalgesia in the mouse model of fibromyalgia through the signaling pathways involving substance P and ASIC3-containing ion channels in muscle afferents. NSAIDs should be cautiously used during tUS treatment.

Keywords: Therapeutic ultrasound; acid-sensing ion channel 3; fibromyalgia; substance P.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acid Sensing Ion Channels / genetics
Acid Sensing Ion Channels / metabolism
Analgesia*
Animals
Anti-Inflammatory Agents, Non-Steroidal / adverse effects
Fibromyalgia* / drug therapy
Hyperalgesia / drug therapy
Hyperalgesia / etiology
Hyperalgesia / metabolism
Mice
Pain
Substance P
Ultrasonic Therapy*

Substances

Substance P
Acid Sensing Ion Channels
Anti-Inflammatory Agents, Non-Steroidal