Abstract
Many scientists are seeking better therapies for treating fibromyalgia (FM) pain. We used a mouse model of FM to determine if ASIC3 and its relevant signaling pathway participated in FM pain. We demonstrated that FM-induced mechanical hyperalgesia was attenuated by electroacupuncture (EA). The decrease in fatigue-induced lower motor function in FM mice was also reversed by EA. These EA-based effects were abolished by the opioid receptor antagonist naloxone and the adenosine A1 receptor antagonist rolofylline. Administration of opioid receptor agonist endomorphin (EM) or adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) has similar results to EA. Similar results were also observed in ASIC3−/− or ASIC3 antagonist (APETx2) injected mice. Using western blotting, we determined that pPKA, pPI3K, and pERK were increased during a dual acidic injection priming period. Nociceptive receptors, such as ASIC3, Nav1.7, and Nav1.8, were upregulated in the dorsal root ganglion (DRG) and spinal cord (SC) of FM mice. Furthermore, pPKA, pPI3K, and pERK were increased in the central thalamus. These aforementioned mechanisms were completely abolished in ASIC3 knockout mice. Electrophysiological results also indicated that acid potentiated Nav currents through ASIC3 and ERK pathway. Our results highlight the crucial role of ASIC3-mediated mechanisms in the treatment of FM-induced mechanical hyperalgesia.
Highlights
Acid-sensing ion channel 3 (ASIC3), the most sensitive ion channel for acid sensation, is mainly localized in peripheral sensory neurons, especially the dorsal root ganglion (DRG), and typically associated with several pain conditions[14,15]
We showed that the analgesic effect of EA was blocked by the opioid antagonist naloxone (Fig. 1D, n = 10) and adenosine antagonist rolofylline (Fig. 1E, n = 10)
The pPKA, pPI3K, and pERK signaling pathway was potentiated in the DRG and spinal cord (SC) during acid injection-induced hyperalgesia priming
Summary
Acid-sensing ion channel 3 (ASIC3), the most sensitive ion channel for acid sensation, is mainly localized in peripheral sensory neurons, especially the DRG, and typically associated with several pain conditions[14,15]. Nav1.8 is the main target for a diverse array of inflammatory mediators that act through a number of second-messenger pathways, including PKA26,28, PKC26,30, and extracellular signal-regulated kinase[26,31]. Several molecules, such as N-methyl-D-aspartate receptors (NMDARs), ASIC3, TRPV1, calcium channels (Cav), and substance P (SP), have been implicated in mouse models of FM pain[12,13,21,32,33]. EA at acupoint ST36 reliably reduced dual acidic saline-induced mechanical hyperalgesia and motor dysfunction via ASIC3-Nav1.7/Nav1.8 signaling pathways. This study provides novel and detailed molecular mechanisms behind the use of EA to treat FM-related mechanical hyperalgesia
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