Signaling Pathways from Cannabinoid Receptor-1 Activation to Inhibition of N-Methyl-D-Aspartic Acid Mediated Calcium Influx and Neurotoxicity in Dorsal Root Ganglion

Although the activation of cannabinoid receptor-1 (CB1) recep-tors by cannabinoids is known to inhibit neuronal hyperexcit-ability and reduce excitotoxic cell death, the mechanistic links between these two actions remain elusive. We tested the hy-pothesis that activation of CB1 receptors inhibits N-methyl-D-aspartic acid (NMDA)-mediated calcium influx and cell death via the inositol triphosphate (IP3) signaling pathway in both primary dorsal root ganglia neurons and a cultured neuronal cell line (F-11 cells). These cells were pretreated with the cannabi-noid agonist (R)-()-[2,3-dihydro-5-methyl-3-(4-morpholinylm-ethyl)pyrrolo[1,2,3-de)-1,4-benzoxazin-6-yl]-1-napthalenyl-methanone (R-()-WIN 55,212-2; WIN) before exposure to NMDA. Concentrations of cytosolic calcium were measured with the ratiometric calcium indicator, Fura-2, and cell deat