Several studies have demonstrated that cannabinoid receptor ligands modulate ion conductance via the capsaicin sensitive transient receptor potential vanilloid type 1 (TRPV1) channel. Recent findings have demonstrated co-localization of TRPV1 and cannabinoid receptor 1 (CB1) in rat dorsal root ganglia. We found that intraplantar administration of capsaicin evoked a dose-dependent and time-related foot flick behavior in ICR and wild type mice (WT), but not in null mutant mice lacking CB1 (Cnr1^-/-). Capsaicin-induced plasma extravasation in the hindpaw and release of CGRP in the dorsal lumbar spinal cord were significantly reduced in Cnr1^-/- as compared to WT mice. In the skin-nerve preparation, capsaicin induced significantly fewer action potentials in C fibers from Cnr1^-/- mice compared to WT mice. Systemic administration of the inverse agonist for CB1, SR141716, prior to intraplantar capsaicin in ICR mice resulted in a dose-related inhibition of capsaicin-induced flinching, which was reversed by pre-treating the animals with an activator of phospholipase Cß (PLCß). Pre-treatment with a PLC inhibitor blocked capsaicin-induced flinching in ICR mice in a dose-dependent manner. Capsaicin-induced flinching was restored in Cnr1^-/- mice when they were pre-treated with galanin or bradykinin, which are known to sensitize TRPV1. These data suggest that CB1 receptors are tonically active such that they maintain appropriate levels of PIP2 by activating PLCß, which preserves the TRPV1 channel in a capsaicin-sensitive state.