Distinct Interactions of Cannabinol and Its Cytochrome P450-Generated Metabolites with Receptors and Sensory Neurons

Interest in nonpsychotropic
cannabinoids like cannabinol
(CBN)
is increasing for pain therapy. This study delivers critical insights
into CBN’s metabolism and pharmacological effects, uncovering
its therapeutic potential for pain reduction. Using metabolomics,
we identify CBN-11-OH as the dominant metabolite, with lower levels
of CBN-1′-OH and CBN-quinone. Computational simulations reveal
CBN’s stability at the CYP2C9 active site, driving hydroxy
metabolite formation. We report the intricate biotransformation of
CBN by multiple cytochrome P450 enzymes. CBN and its metabolites exhibit
mild anti-inflammatory effects in microglial cells, though less potent
than cannabigerol and cannabichromene. Receptor activation assays
further reveal that CBN-1′-OH acts as a partial CB1 agonist,
while CBN and its metabolites antagonize CB1 and CB2 receptors. Notably,
CBN and CBN-11-OH elevate intracellular Ca2+ levels in
dorsal root ganglia sensory neuronsan effect linked to potential
pain relief. These findings lay the groundwork for harnessing CBN
and its metabolites in novel pain therapeutics.