Signaling pathways involved in the development of cannabinoid tolerance.

Considerable plasticity exists in the endogenous cannabinoid system, as evidenced by the high degree of tolerance that develops following repetitive exposure to exogenously administered cannabinoid receptor agonists. This tolerance development is accompanied by cannabinoid CB(1) receptor downregulation and attenuation of G-protein activation. The biological processes responsible for CB(1) receptor downregulation remain to be fully understood. However, recent evidence suggests that several protein kinases participate in the development of cannabinoid tolerance. These observations implicate a role for protein kinases in cannabinoid signaling pathways. It remains to be established whether these protein kinases are directly involved in CB(1) receptor regulation or whether they contribute to tolerance by modulating additional signaling pathways.