CB2cannabinoid receptor-selective agonists are promising candidates for the treatment of pain. CB2receptor activation inhibits acute, inflammatory, and neuropathic pain responses but does not cause central nervous system (CNS) effects, consistent with the lack of CB2receptors in the normal CNS. To date, there has been virtually no information regarding the mechanism of CB2receptor-mediated inhibition of pain responses. Here, we test the hypothesis that CB2receptor activation stimulates release from keratinocytes of the endogenous opioid-endorphin, which then acts atopioid receptors on primary afferent neurons to inhibit nociception. The antinociceptive effects of the CB2receptor-selective agonist AM1241 were prevented in rats when naloxone or anti-serum to-endorphin was injected in the hindpaw where the noxious thermal stimulus was applied, suggesting that endorphin is necessary for CB2receptor-mediated antinociception. Futher, AM1241 did not inhibit nociception in-opioid receptor-deficient mice. Hindpaw injection of-endorphin was sufficient to produce antinociception. AM1241 stimulated-endorphin release from rat skin tissue and from cultured human keratinocytes. This stimulation was prevented by AM630, a CB2cannabinoid receptor-selective antagonist and was not observed in skin from CB2cannabinoid receptor-deficient mice. These data suggest that CB2receptor activation stimulates release from keratinocytes of-endorphin, which acts at local neuronal-opioid receptors to inhibit nociception. Supporting this possibility, CB2 immunolabeling was detected on-endorphin-containing keratinocytes in stra-tum granulosum throughout the epidermis of the hindpaw. This mechanism allows for the local release of-endorphin, where CB2receptors are present, leading to anatomical specificity of opioid effects.