Inhibition of sodium conductance by cannabigerol contributes to a reduction of dorsal root ganglion neuron excitability

Background and Purpose: Cannabigerol (CBG), a non-psychotropic phytocannabinoid and a precursor of Delta(9) -tetrahydrocannabinol and cannabidiol, has been suggested to act as an analgesic. A previous study reported that CBG (10 pM) blocks voltage-gated sodium (Na-v) currents in CNS neurons, although the underlying mechanism is not well understood. Genetic and functional studies have validated Na(v)1.7 channels as an opportune target for analgesic drug development. The effects of CBG on Na(v)1.7 channels, which may contribute to its analgesic properties, have not been previously investigated. Experimental Approach: To determine the effects of CBG on Na-v 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 similar to 10-fold state-dependent Na-v channel inhibitor (K-I-K-R : similar to 2-20 mu M) with an average Hill-slope of similar to 2. We determined that, at lower concentrations, CBG predominantly blocks sodium G(max) 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 Na(v)1.7 channels in DRG neurons may underlie CBG-induced neuronal hypoexcitability. As most Na(v)1.7 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 Na(v)1.7 channels, compared with other Na-v channels (via G(max) block).

Automated summary

CBG selectively inhibits Na(v)1.7 channels in DRG neurons, contributing to its analgesic properties. At lower concentrations, CBG blocks sodium G(max) and slows recovery from inactivation, while higher concentrations also induce a hyperpolarizing shift in the half-voltage of inactivation. Experimental results suggest that CBG attenuates DRG excitability.