Cannabinoid Modulation of Perivascular Sympathetic and Sensory Neurotransmission

Cannabinoids are signalling molecules which elicit their vascular effects mainly via G protein-coupled CB1 receptors and transient receptor potential (TRP) channels (chiefly vanilloid TRPV1 receptors). Cannabinoids can act at prejunctional CB1 receptors to inhibit perivascular sympathetic neurotransmission. The effects of cannabinoids on perivascular capsaicin-sensitive sensory nerves are more complex. Certain cannabinoids can activate sensory nerves through actions on TRPV1 receptors and other TRP channels, which leads to sensory neurotransmitter release (mainly calcitonin gene-related peptide) and vasorelaxation. However, activation of TRP/TRPV1 channels can also lead to desensitization and loss of sensory nerve activity. Concentration and time of exposure may be critical in determining which of these opposite effects of cannabinoids prevails. In addition, there is evidence for the expression of CB1 receptors on perivascular capsaicin-sensitive sensory nerves, coupled to inhibition of neurotransmitter release. There is evidence that the archetypal cannabinoid anandamide is released as a neurotransmitter in the central nervous system, and from sensory ganglia, but a release of cannabinoids from perivascular nerves has yet to be clearly demonstrated. Hence, with regard to perivascular nerves, cannabinoids appear to act principally as prejunctional modulators of neurotransmission. The diverse prejunctional effects of cannabinoids may be novel targets for therapies designed to treat vascular disease.