Nonpsychoactive Cannabinoid Action on 5-HT3 and Glycine Receptors

The 5-HT3 and glycine receptors are pentameric ion channels belonging to a Cys-loop ligand-gated ion channel superfamily. While the glycine receptors can mediate fast inhibitory synaptic transmission, the 5-HT3 receptors are involved in both excitatory and inhibitory synaptic transmission in the central and peripheral nervous system. These receptors play important roles in several physiological and pathological processes such as vomiting reflex, neuromotor activity, pain process, reward mechanism of drugs of abuse, cognition, and anxiety control. Emerging evidence has identified both receptors as primary targets for the action of nonpsychoactive cannabinoids in the brain. Psychoactive and nonpsychoactive cannabinoids alter the amplitudes of 5-hydroxytryptamine and glycine-activated currents in native neurons and in cell lines expressing recombinant 5-HT3 and glycine receptors through CB1 and CB2 receptor-independent mechanisms. However, little is known about molecular mechanisms and behavioral implications of this specific cannabinoid modulation. Results from recent studies have shed light on the molecular basis of nonpsychoactive cannabinoid modulation of glycine receptors. Evidence has also emerged to suggest that cannabinoid modulation of glycine receptors contributes to some of the cannabis-induced analgesic effect. This research direction could help develop novel therapeutic agents for the treatment of pain and other diseases. This chapter summarizes recent research progress in our knowledge about the mechanisms and in vivo consequence of cannabinoid modulation of 5-HT3 and glycine receptors.