Objective It has been reported that EA-produced analgesia is mediated by endogenous opioid systems in uninjured and inflammatory pain animal models.However, whether CB2Rs activation contributes to 2Hz EA regulation of β-endorphin in inflamed skin tissue of rats was still unknown.Here we determined the effects ofCB2R activation and EA on the expression and distribution patterns of β-endorphin in inflamed skin tissues and the role of peripheral MORs in the analgesia effect.Methods Inflammatory pain was induced by injection of complete Freunds adjuvant into the left hindpaw of rats.Thermal hyperalgesia was tested with a radiant heat stimulus, and mechanical allodynia was quantified using yon Frey filaments.The mRNA level of POMC and protein level of β-endorphin were quantified by using real-time PCR and Western blotting, respectively.The distribution of β-endorphin on keratinocytes and immune cells recruited to the inflamed skin tissues was detected by using double-immunofluorescence labeling.Results (1) The CB2R agonist AM1241 and 2 Hz EA applied to GB30 and GB34 significantly reduced thermal hyperalgesia and mechanical allodynia induced by CFA injection.The specific CB2R antagonist AM630 and selective MOR antagonist β-funaltrexamine significantly attenuated the antinociceptive effect 2Hz EA.(2) AM1241 and 2Hz EA significantly increased the mRNA level of POMC and protein level of β-endorphin in inflamed skin tissues.Pretreatment with AM630 significantly reversed the excitatory effect of EA on β-endorphin expression.(3)Through activation of CB2Rs, AM1241 and 2Hz EA significantly increased the number of keratinocytes, macrophages, and T-lymphocytes with β-endorphin-immunoreactivity in the inflamed skin tissue.Conclusion EA primarily potentiates the expression of β-endorphin on keratinocytes and infiltrating inflammatory cells at the site of inflammation through activation of CB2Rs.β-endorphin in turn activates peripheral MORs to reduce inflammatory pain.