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 (EC_50∼3.7 μ m), 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 μ m), 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. [ABSTRACT FROM AUTHOR]