Methanandamide activation of a novel current in mouse trigeminal ganglion sensory neurons in vitro

Anandamide is an endogenous agonist for cannabinoid receptors and produces analgesia by acting at these receptors in several sites in the brain and peripheral nervous system. Anandamide is also an agonist at the TRPV1 receptor, a protein that serves as an important integrator of noxious stimuli in sensory neurons. Although anandamide actions at CB1 and TRPV1 receptors can explain many of its effects on sensory neurons, some apparently CB1- and TRPV1-independent effects of anandamide have been reported. To explore possible mechanisms underlying these effects we examined the actions of the stable anandamide analog methanandamide on the membrane properties of trigeminal ganglion neurons from mice with TRPV1 deleted. We found that methanandamide and anandamide activate a novel current in a subpopulation of small trigeminal ganglion neurons. Methanandamide activated the current (EC50 2 μM) more potently than it activates TRPV1 under the same conditions. The methanandamide-activated current reverses at 0 mV and does not inactivate at positive potentials but declines rapidly at negative membrane potentials. Activation of the current is not mediated via cannabinoid receptors and does not appear to involve G proteins. The phytocannabinoid Δ9-tetrahydrocannabinol, the endocannabinoid-related molecules N-arachidonoyl dopamine and N-arachidonoyl glycine and the non-specific TRPV channel activator 2-aminoethoxydiphenyl borate do not mimic the effects of methanandamide. The molecular identity of the current remains to be established, but we have identified a potential new effector for endocannabinoids in sensory neurons, and activation of this current may underlie some of the previously reported CB1 and TRPV1-independent effects of these compounds.