Exosomal Adiponectin Plays a Role in Electroacupuncture Analgesia by Activating the Adiponectin Receptor 1 to Inhibit Pain-Related Pathways in Mice Brain.

Fibromyalgia (FM) is a difficult-to-cure disease, and finding effective pain management methods is crucial for providing clinicians and healthcare. Adiponectin (ADP) is considered a peripheral metabolic hormone, but its role in the central nervous system remains unknown, especially in pain management. Electroacupuncture (EA) has long been scientifically proven as an effective therapy for pain relief. We aimed to investigate the molecular mechanisms in the thalamus, somatosensory cortex, anterior cingulate cortex, and medial prefrontal cortex during intermittent cold stress (ICS)-induced FM in mice, and the inhibitory effects of 2-Hz EA stimulation or intracerebral ventricle (ICV) injection of ADP on this FM model. Results showed that the FM group significantly produced mechanical and thermal hyperalgesia (∗p < 0.05, n = 9), while the FM + EA and FM + ADP groups showed significant reductions in mechanical and thermal hyperalgesia (#p < 0.05, n = 9). The extracellular vesicles high mobility group box 1 and S100 calcium-binding protein B (mediators in inflammation) were detected increased while ADP was found decreased, which can be reversed by EA but not ICV injection of ADP. Western blot analysis revealed a significant decrease in adiponectin receptor 1 (AdipoR1) and related signaling pathways after ICS-induced FM hyperalgesia. However, encouragingly, in the FM + EA group, EA treatment effectively increased AdipoR1 expression. Similar results were observed in the FM + ADP group. This trend was also observed in its downstream pathways including APPL1, SIRT1, AMPKα, and PPARα. We further found a significant increase in pain-related pPI3K-pAkt-pmTOR and pNFκB pathways in the FM group, and EA or ICV-administered ADP treatment inhibited these increases. Our results confirm that 2-Hz EA can treat FM pain, and its mechanism of action is through the activation of AdipoR1 and its downstream related molecular pathways.