Synthetic cannabinoid CP-55,940 induces apoptosis in a human skeletal muscle model via regulation of CB receptors and L-type Ca channels.

Rhabdomyolysis has been reported in patients who abuse synthetic cannabinoids. However, no studies have yet assessed whether these cases reflect the direct cytotoxicity of synthetic cannabinoids on skeletal muscle, a possibility that the present study sought to address. Specifically, this study investigated the cytotoxicity of the synthetic cannabinoid CP-55,940, a compound that acts equally on both types of cannabinoid receptors (CB and CB), in a human embryonic rhabdomyosarcoma (RD) cell line. Exposure of these cells to CP-55,940 resulted in concentration-dependent decreases in cell viability. These effects were attenuated by pre-incubation with AM251 (30 µM), a selective CB receptor antagonist, but not by pre-incubation with AM630 (30 µM), a selective CB receptor antagonist. Following treatment with CP-55,940, RD cells exhibited apoptosis, as indicated by the accumulation of annexin-V, activation of caspase-3, and a loss of the mitochondrial membrane potential. Additionally, CP-55,940 treatment of RD cells led to increases in intracellular Ca levels. CP-55,940-induced cell death was significantly attenuated in the absence of extracellular Ca, and was partially decreased by pre-incubation with verapamil (5 µM) or diltiazem (5 µM), compounds that block the L-type Ca channel. Our results indicate that the cytotoxicity of CP-55,940 towards RD cells (skeletal muscle cells) is mediated by the CB receptor, but not by the CB receptor. Our results further suggest that calcium influx through the L-type channel may play an important role in the apoptosis induced by these compounds.