Br J Pharmacol. 2022 Mar 16. doi: 10.1111/bph.15833. Online ahead of print.
BACKGROUND AND PURPOSE: Cannabigerol (CBG), a non-psychotropic phytocannabinoid and a precursor for ∆9-tetrahydrocannabinol and cannabidiol, has been suggested to act as an analgesic. A previous study reported that CBG (10 μM) blocks voltage-gated sodium (Nav) currents in CNS neurons; however, the underlying mechanism is not well-understood. Genetic and functional studies have validated Nav1.7 as an opportune target for analgesic drug development. The effects of CBG on Nav1.7 channels, which may contribute to its analgesic properties, have not been previously investigated.
EXPERIMENTAL APPROACH: To determine the effects of CBG on Nav channels, we used stably transfected HEK cells and primary dorsal root ganglion (DRG) neurons to characterize compound effects using experimental and computational techniques. These included patch-clamp, multielectrode array, and action potential modelling.
KEY RESULTS: We found that CBG is a ~10-fold state-dependent Nav inhibitor (KI -KR : ~2-20 μM) with an average Hill-slope of ~2. We determined that at lower concentrations, CBG predominantly blocks sodium Gmax and slows recovery from inactivation; however, as the concentration is increased, CBG also induces a hyperpolarizing shift in half-voltage of inactivation. Our modeling and multielectrode array recordings suggest that CBG attenuates DRG excitability.
CONCLUSIONS AND IMPLICATIONS: Inhibition of Nav1.7 in DRG neurons may underlie CBG-induced neuronal hypoexcitability. As most Nav1.7 channels are inactivated at DRG resting membrane potential, they are more likely to be inhibited by lower CBG concentrations, suggesting functional selectivity against Nav1.7 compared to other Navs (via Gmax block).