Minor cannabinoids CBD, CBG, CBN, and CBC differentially modulate sensory neuron activation

The use of minor cannabinoids has been advanced, in part, by the idea of providing relief from pain and inflammation without the unwanted psychogenic effects associated with delta-9-tetrahydro-cannabinol (Δ⁹THC). With a focus on peripheral nociception, 4 common minor cannabinoids: cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), and cannabichromene (CBC) were studied in primary cultures of mouse dorsal root ganglion (DRG) neurons. We queried whether calcium responses induced by the 4 cannabinoids differed in potency of activation, neuronal size preference, and dose-response relationships. Additionally, we determined the dependence of CBD and CBN on key channel receptors that are known to mediate pain and/or antinociception. Individually, CBD, CBG, and CBC directed greater response magnitudes when compared with CBN. All 4 minor cannabinoids activated overlapping size populations of sensory neurons. CBD and CBG activated the widest range of DRG neuron sizes (smaller-larger), overlapping with smaller capsaicin-sensitive neurons. In contrast, CBN and CBC activated predominantly larger sensory neurons. CBD diverged from other minor cannabinoids in directing a linear dose-response profile, whereas CBG and CBC directed sigmoidal profiles and CBN activated DRG neurons with an inverted U-shaped dose-response relationship. CBD-induced activation of DRG neurons was dependent on coexpression of the nociceptive channel transient receptor potential cation channel subfamily Vanilloid member 1 (TRPV1) plus cannabinoid receptor 1 (CB₁R), whereas CBN-induced activation was independent of TRPV1 and CB₁R. Overall, we observed that minor cannabinoids CBD, CBG, CBN, and CBC directed unique activation properties across a diverse population of sensory neurons. Such differences underlie the hypothesis that a combination of minor cannabinoids can direct complementary antinociceptive activity. SIGNIFICANCE STATEMENT: Minor cannabinoids CBD, CBG, CBN, and CBC differ in their dose-dependent properties of sensory neuronal activation. CBD-induced activation of small to large sensory neurons was dependent on coexpression of the nociceptive channel TRPV1 plus CB₁R and directed a linear dose-response profile. In contrast, CBN activated predominantly larger sensory neurons in an inverted U-shaped dose-response profile and was independent of TRPV1 and CB₁R. A combination of minor cannabinoids is hypothesized to direct complementary antinociceptive activity.