Cannabidiol activation of vagal afferent neurons requires TRPA1

Vagal afferent neurons abundantly express excitatory transient receptor potential (TRP) channels, which strongly influence afferent signaling. Cannabinoids have been identified as direct agonists of TRP channels, including TRPA1 and TRPV1, suggesting that exogenous cannabinoids may influence vagal signaling via TRP channel activation. The diverse therapeutic effects of electrical vagus nerve stimulation also result from administration of the nonpsychotropic cannabinoid, cannabidiol (CBD); however, the direct effects of CBD on vagal afferent signaling remain unknown. We investigated actions of CBD on vagal afferent neurons, using calcium imaging and electrophysiology. CBD produced strong excitatory effects in neurons expressing TRPA1. CBD responses were prevented by removal of bath calcium, ruthenium red, and the TRPA1 antagonist A967079, but not the TRPV1 antagonist SB366791, suggesting an essential role for TRPA1. These pharmacological experiments were confirmed using genetic knockouts where TRPA1 KO mice lacked CBD responses, whereas TRPV1 knockout (KO) mice exhibited CBD-induced activation. We also characterized CBD-provoked inward currents at resting potentials in vagal afferents expressing TRPA1 that were absent in TRPA1 KO mice, but persisted in TRPV1 KO mice. CBD also inhibited voltage-activated sodium conductances in A-fiber, but not in C-fiber afferents. To simulate adaptation, resulting from chronic cannabis use, we administered cannabis extract vapor daily for 3 wk. Cannabis exposure reduced the magnitude of CBD responses, likely due to a loss of TRPA1 signaling. Together, these findings detail a novel excitatory action of CBD at vagal afferent neurons, which requires TRPA1 and may contribute to the vagal mimetic effects of CBD and adaptation following chronic cannabis use.NEW & NOTEWORTHY CBD usage has increased with its legalization. The clinical efficacy of CBD has been demonstrated for conditions including some forms of epilepsy, depression, and anxiety that are also treatable by vagus nerve stimulation. We found CBD exhibited direct excitatory effects on vagal afferent neurons that required TRPA1, were augmented by TRPV1, and attenuated following chronic cannabis vapor exposure. These effects may contribute to vagal mimetic effects of CBD and adaptation after chronic cannabis use.