DER-SHENG HANLee, Cheng HanCheng HanLeeShieh, Yih DarYih DarShiehKE-VIN CHANGLin, Shing HongShing HongLinChu, Ya CherngYa CherngChuJAW-LIN WANGChen, Chih ChengChih ChengChen2023-06-092023-06-092023-01-0115265900https://scholars.lib.ntu.edu.tw/handle/123456789/632048Therapeutic 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.enacid-sensing ion channel 3 | fibromyalgia | substance P | Therapeutic ultrasound[SDGs]SDG3journal article10.1016/j.jpain.2023.04.003370547672-s2.0-85159232692https://api.elsevier.com/content/abstract/scopus_id/85159232692