Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation

Aim:  Plant cannabinoids, like Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), activate/desensitize thermosensitive transient receptor potential (TRP) channels of vanilloid type-1 or -2 (TRPV1 or TRPV2). We investigated whether cannabinoids also activate/desensitize two other ‘thermo-TRP’s’, the TRP channels of vanilloid type-3 or -4 (TRPV3 or TRPV4), and if the TRPV-inactive cannabichromene (CBC) modifies the expression of TRPV1–4 channels in the gastrointestinal tract. Methods:  TRP activity was assessed by evaluating elevation of [Ca2+]i in rat recombinant TRPV3- and TRPV4-expressing HEK-293 cells. TRP channel mRNA expression was measured by quantitative RT-PCR in the jejunum and ileum of mice treated with vehicle or the pro-inflammatory agent croton oil. Results:  (i) CBD and tetrahydrocannabivarin (THCV) stimulated TRPV3-mediated [Ca2+]i with high efficacy (50–70% of the effect of ionomycin) and potency (EC50∼3.7 μm), whereas cannabigerovarin (CBGV) and cannabigerolic acid (CBGA) were significantly more efficacious at desensitizing this channel to the action of carvacrol than at activating it; (ii) cannabidivarin and THCV stimulated TRPV4-mediated [Ca2+]i with moderate-high efficacy (30–60% of the effect of ionomycin) and potency (EC50 0.9–6.4 μm), whereas CBGA, CBGV, cannabinol and cannabigerol were significantly more efficacious at desensitizing this channel to the action of 4-α-phorbol 12,13-didecanoate (4α-PDD) than at activating it; (iii) CBC reduced TRPV1β, TRPV3 and TRPV4 mRNA in the jejunum, and TRPV3 and TRPV4 mRNA in the ileum of croton oil-treated mice. Conclusions:  Cannabinoids can affect both the activity and the expression of TRPV1–4 channels, with various potential therapeutic applications, including in the gastrointestinal tract.