Non-psychotropic phytocannabinoid interactions with voltage-gated sodium channels: An update on cannabidiol and cannabigerol

Abstract

Phytocannabinoids, found in the plant, Cannabis sativa, are an important class of natural compounds with physiological effects. These compounds can be generally divided into two classes: psychoactive and non-psychoactive. Those which do not impart psychoactivity are assumed to predominantly function via endocannabinoid receptor (CB) -independent pathways and molecular targets, including other receptors and ion channels. Among these targets, the voltage-gated sodium (Nav) channels are particularly interesting due to their well-established role in electrical signalling in the nervous system. The interactions between the main non-psychoactive phytocannabinoid, cannabidiol (CBD), and Nav channels were studied in detail. In addition to CBD, cannabigerol (CBG), is another non-psychoactive molecule implicated as a potential therapeutic for several conditions, including pain via interactions with Nav channels. In this mini review, we provide an update on the interactions of Nav channels with CBD and CBG.

Functionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol

“…Like cannabidiol (CBD) and cannabigerol (CBG), CBN has been suggested as an anti-inflammatory and analgesic agent 4 , 5 . Previous studies have reported that CBN (dosed at 1 mg/ml) can mitigate myofascial pain in rats 6 .…”

“…THC was first discovered to interact with these receptors 11 . Recently, other non-psychotropic phytocannabinoids, including CBD and CBG, were shown to interact with several other targets 1 , 12 , including multiple receptors, ion channels, and the cell membrane itself 4 . Like CBD and CBG 4 , CBN modulates several transient receptor potential (TRP) channels 13 .…”

“…Recently, other non-psychotropic phytocannabinoids, including CBD and CBG, were shown to interact with several other targets 1 , 12 , including multiple receptors, ion channels, and the cell membrane itself 4 . Like CBD and CBG 4 , CBN modulates several transient receptor potential (TRP) channels 13 . Although CBN is an agonist at both CB receptors, it has been classified as a non-psychoactive cannabinoid that possess sedative-like properties 3 .…”

“…Among the potential therapeutic applications for CBN, its analgesic effects are particularly interesting. Because CBN shares analgesic features and diversity of known molecular targets with both CBD and CBG, we sought to determine if CBN also modulates voltage-gated sodium (Nav) channels, which have a well-stablished role in pain physiology and are implicated as vital to the CB-independent cannabinoid pathway 4 , 14 . Nav1.7 is regarded as the major Nav isoform that sets the gain for nociception in DRG neurons 15 – 18 and is being explored as a target for analgesic drug development.…”

“…Previous studies thoroughly described the interactions between Nav channels and CBD/CBG. CBD was shown to directly block Nav channels as well as indirectly inhibit their activity through modulating bio-membrane stiffness; CBG was shown to inhibit maximal sodium conductance ( G max ) more potently than stabilizing inactivation 4 . Given the similarities in the structures and other features of CBD/CBG with CBN, we used earlier observations of CBD/CBG to guide our investigation of CBN in this study.…”