Inhibition of sodium conductance by cannabigerol contributes to a reduction of dorsal root ganglion neuron excitability
Go to journal
Background and Purpose: Cannabigerol (CBG), a non-psychotropic phytocannabinoid and a precursor of ∆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, although the underlying mechanism is not well understood. Genetic and functional studies have validated Nav1.7 channels 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: CBG is a ~10-fold state-dependent Nav channel 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 the half-voltage of inactivation. Our modelling and multielectrode array recordings suggest that CBG attenuates DRG excitability. Conclusions and Implications: Inhibition of Nav1.7 channels in DRG neurons may underlie CBG-induced neuronal hypoexcitability. As most Nav1.7 channels are inactivated at the resting membrane potential of DRG neurons, they are more likely to be inhibited by lower CBG concentrations, suggesting functional selectivity against Nav1.7 channels, compared with other Nav channels (via Gmax block).