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Significance Pain remains an unmet medical need due to the ineffectiveness or significant side effects of current pain therapies. Peripheral neurostimulation has been used to relieve pain for decades, but its mechanism(s) remain unsettled. Here, we established an animal model of median nerve stimulation by electrically stimulating the PC6 (Neiguan) acupoint of mice (MNS-PC6). We found MNS-PC6 can release an endogenous neuropeptide (orexin) from the hypothalamus to inhibit pain responses in mice through an endocannabinoid (an endogenous lipid functioning like chemicals from cannabis) that reduces the inhibitory (GABAergic) control in a midbrain pain-control region (the periaqueductal gray). Importantly, MNS-PC6–induced pain relief is endogenous opioid independent. Thus, MNS-PC6 may provide an alternative strategy for pain management in opioid-tolerant patients.

Median nerve stimulation induces analgesia via orexin-initiated endocannabinoid disinhibition in the periaqueductal gray