Cannabidiol activation of vagal afferent neurons requires TRPA1

Abstract

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 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 non-psychotropic 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 while TRPV1 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 C-fiber afferents. To simulate adaptation resulting from chronic cannabis use, we administered cannabis extract vapor daily for three weeks. 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.

Transient Receptor Potential (TRP) and Thermoregulation in Animals: Structural Biology and Neurophysiological Aspects

“…One of its main contributions is the transduction of nociceptive stimuli in the primary afferent nerve endings during signal transmission in the dorsal horn spinal neurons, but it also participates in episodes of neurogenic inflammation [ 48 ]. In clinical medicine, this receptor is being studied due to its activation and therapeutic effect under the administration of cannabidiol (CBD) [ 50 ].…”

A molecular explanation of cardiovascular protection through abnormal cannabidiol: Involving the dysfunctional β‐adrenergic and ATP‐sensitive K+ channel activity in cardiovascular compromised preterm infants

“…Furthermore, recent studies have examined the crucial function of TRPA1 that plays an important role in mediating the excitatory effects of CBD in vagal neurons, and have shown that (1) CBD increases calcium intracellular from an external source and induces depolarizations; (2) this responsiveness requires TRPA1, but is improved by expression of TRPV1. [33] Abn-CBD is a synthetic CBD regioisomer that has not seen noticeable behavioral consequences in preliminary studies. [34][35][36] In comparison to most other cannabinoids, these causes vasodilator effects reduce blood pressure, and stimulates cell differentiation, cell proliferation, and mitogen-activated protein kinase activation in microglia, but without any psychoactive effects.…”

“…[105][106][107] Although prompt reperfusion restores oxygen and substrates needed for aerobic ATP generation and optimizes extracellular pH by cleaning H+ accumulated, reperfusion itself tends to have adverse effects. Furthermore, recent studies have examined the crucial function of TRPA1 that plays an important role in mediating the excitatory effects of Abn-CBD in vagal neurons, and have shown that (1) Abn-CBD increases calcium intracellular from an external source and induces depolarizations; (2) this responsiveness requires TRPA1, but is improved by expression of TRPV1 [33] that contribute in further enhancing reflex towards adrenergic flux may increase the responsiveness towards Gαs protein-mediated cardiac depolarization. In this way, avoidance of KATP opening has been described as a cardioprotection paradigm for heart hypoxia-ischemic injury in cardiovascular compromise preterm infants.…”

“…Furthermore, recent studies have examined the crucial function of TRPA1 that plays an important role in mediating the excitatory effects of CBD in vagal neurons, and have shown that (1) CBD increases calcium intracellular from an external source and induces depolarizations; (2) this responsiveness requires TRPA1, but is improved by expression of TRPV1. [ 33 ]…”

A study of abnormal cannabidiols system‐mediated cardiovascular protection in disrupted gut/brain axis associated depression

“…Marichal-Cancino et al 61 identified an associated effect of GPR55 as CBD blocked an LPI inhibition of noradrenalines-related vasopressor responses, which indicated that this receptor could play a role in the outcomes of CBD. Recently, however, studies have investigated the key role of transient receptor potential ankyrin1 which is an essential factor in facilitating the excitatory effects in vagal neurons of CBD, and have shown that CBD raises the intracellular calcium from external sources to cause depolarizations 62 (Figure 2).…”