Adiponectin regulates electroacupuncture-produced analgesic effects in association with a crosstalk between the peripheral circulation and the spinal cord

[Display omitted] •The deletion of APN significantly reduces EA analgesia.•Intrathecal administration of APN mimics the analgesic effects of EA.•EA increases APN accumulation in the spinal cord coming from blood vessels.•Spinal adipoR2 dominantly mediates APN- and EA-produced analgesic effects.•Spinal activation of AMPK is required for EA-APN-AdipoR2-produced analgesic effects. Neurotransmitter-mediated acupuncture analgesia has been widely studied in nervous systems. It remains largely unclear if peripheral substances are involved the acupuncture analgesia. Adiponectin (APN), a circulating adipokine, shows analgesic effects. The study aimed to examine whether APN regulates analgesic effects of electroacupuncture (EA) in the complete Freund’s adjuvant (CFA)-induced mouse model. APN wild type (WT) and knockout (KO) mouse were employed in the study. We found that EA attenuates the CFA-induced pain as demonstrated by the Hargreaves thermal test and the von Frey filament test. The deletion of APN significantly reduced the acupuncture analgesia in the CFA-treated APN KO mice while the intrathecal administration of APN mimicked the analgesic effects of EA. We further revealed that EA produced analgesic effects mainly via APN/AdipoR2-mediated AMPK pathway by the siRNA inhibitions of APN receptors (adipoR1/2) in the spinal cord. The immunofluorescence staining analysis showed that EA increased the APN accumulation in spinal cord through the blood circulation. In conclusion, the study indicates a novel mechanism that acupuncture produces analgesic effects at least partially via APN/AdipoR2-AMPK pathway in the spinal cord.