EXCITATORY ACTIONS OF CANNABINOIDS ON VAGAL AFFERENT SIGNALING VIA TRP CHANNELS
Kowalski, Cody William
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Vagal afferent neurons transmit visceral information to the nucleus of the solitary tract (NTS) to regulate cardiovascular, respiratory, and gastrointestinal reflexes. Vagal afferent terminals release most glutamate via spontaneous and asynchronous processes, controlled by cannabinoid-sensitive excitatory transient receptor potential (TRP) channels. Clinical evidence indicates cannabis provokes autonomic effects that may contribute to its therapeutic effects; however, the direct effects of cannabinoids on vagal afferent signaling have not been investigated. This thesis provides the principle investigation into the effects of the exogenous cannabinoids δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on vagal afferent signaling. In Chapter 1, we review the fundamental features of this system and supportive clinical observations. In Chapter 2, we determine that CBD’s excitatory effects require TRPA1, and that expression of TRPV1 enhances this effect. We also determined prevalent afferent C-fibers are resistant to inhibition of voltage-activated sodium channels by CBD. In a vapor-administration model of chronic cannabis use, cannabis exposure attenuated calcium responses to CBD and the specific TRPA1 agonist allyl isothiocyanate (AITC). In Chapter 3, we investigated the effects of CBD on afferent terminals in the NTS. We found that CBD enhanced spontaneous release frequency in TRPA1-expressing afferents, yet reduces spontaneous frequency following genetic deletion of TRPA1; this indicates CBD provokes competing, broadly inhibitory and TRPA1-dependent excitatory effects on spontaneous release, typically resulting in an excitatory net effect. Chronic cannabis exposure attenuated the excitatory effects of CBD, resulting in a neutral net effect. In Chapter 4, we investigated the effects of THC on vagal afferents and their central terminals. We determined that TRPA1 is necessary, but not always sufficient, for THC-provoked calcium responses in vagal afferents. At central terminals, THC bidirectionally modulated spontaneous release frequency, even after chronic cannabis exposure. Chronic cannabis exposure diminished sodium leak currents in all afferents, potentially increasing vagal afferent sensitivity to endogenous factors by increasing the depolarizing effect of current flux. Collectively, these findings demonstrate that exogenous cannabinoids significantly influence vagal afferent signaling, predominantly via TRPA1. Chronic cannabis exposure results in some tolerance to these excitatory effects, but may simultaneously sensitize afferents to activation by endogenous factors by increasing membrane resistance.