Signaling Mechanism of Cannabinoid Receptor-2 Activation-Induced β-Endorphin Release

Activation of cannabinoid receptor-2 (CB2) results in beta-endorphin release from keratinocytes, which then acts on primary afferent neurons to inhibit nociception. However, the underlying mechanism is still unknown. The CB2 receptor is generally thought to couple to Gi/o to inhibit cAMP production, which cannot explain the peripheral stimulatory effects of CB2 receptor activation. In this study, we found that in a keratinocyte cell line, the G beta gamma subunits from Gi/o, but not G alpha s, were involved in CB2 receptor activation-induced beta-endorphin release. Inhibition of MAPK kinase, but not PLC, abolished CB2 receptor activation-induced beta-endorphin release. Also, CB2 receptor activation significantly increased intracellular Ca2+. Treatment with BAPTA-AM or thapsigargin blocked CB2 receptor activation-induced beta-endorphin release. Using a rat model of inflammatory pain, we showed that the MAPK kinase inhibitor PD98059 abolished the peripheral effect of the CB2 receptor agonist on nociception. We thus present a novel mechanism of CB2 receptor activation-induced beta-endorphin release through Gi/o-G beta gamma-MAPK-Ca2+ signaling pathway. Our data also suggest that stimulation of MAPK contributes to the peripheral analgesic effect of CB2 receptor agonists.