De Petrocellis Luciano, Vellani Vittorio, Schiano-Moriello Aniello, Marini Pietro, Magherini Pier Cosimo, Orlando Pierangelo, Di Marzo Vincenzo
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti 80078, Pozzuoli (NA), Italy.
J Pharmacol Exp Ther. 2008 Jun;325(3):1007-15. doi: 10.1124/jpet.107.134809. Epub 2008 Mar 19.
The plant cannabinoids (phytocannabinoids), cannabidiol (CBD), and Delta(9)-tetrahydrocannabinol (THC) were previously shown to activate transient receptor potential channels of both vanilloid type 1 (TRPV1) and ankyrin type 1 (TRPA1), respectively. Furthermore, the endocannabinoid anandamide is known to activate TRPV1 and was recently found to antagonize the menthol- and icilin-sensitive transient receptor potential channels of melastatin type 8 (TRPM8). In this study, we investigated the effects of six phytocannabinoids [i.e., CBD, THC, CBD acid, THC acid, cannabichromene (CBC), and cannabigerol (CBG)] on TRPA1- and TRPM8-mediated increase in intracellular Ca2+ in either HEK-293 cells overexpressing the two channels or rat dorsal root ganglia (DRG) sensory neurons. All of the compounds tested induced TRPA1-mediated Ca2+ elevation in HEK-293 cells with efficacy comparable with that of mustard oil isothiocyanates (MO), the most potent being CBC (EC(50) = 60 nM) and the least potent being CBG and CBD acid (EC(50) = 3.4-12.0 microM). CBC also activated MO-sensitive DRG neurons, although with lower potency (EC(50) = 34.3 microM). Furthermore, although none of the compounds tested activated TRPM8-mediated Ca2+ elevation in HEK-293 cells, they all, with the exception of CBC, antagonized this response when it was induced by either menthol or icilin. CBD, CBG, THC, and THC acid were equipotent (IC(50) = 70-160 nM), whereas CBD acid was the least potent compound (IC(50) = 0.9-1.6 microM). CBG inhibited Ca2+ elevation also in icilin-sensitive DRG neurons with potency (IC(50) = 4.5 microM) similar to that of anandamide (IC(50) = 10 microM). Our findings suggest that phytocannabinoids and cannabis extracts exert some of their pharmacological actions also by interacting with TRPA1 and TRPM8 channels, with potential implications for the treatment of pain and cancer.
此前研究表明，植物大麻素（植物源性大麻素）、大麻二酚（CBD）和Δ⁹-四氢大麻酚（THC）分别可激活香草酸受体1型（TRPV1）和锚蛋白1型（TRPA1）的瞬时受体电位通道。此外，内源性大麻素花生四烯乙醇胺可激活TRPV1，最近还发现它可拮抗对薄荷醇和异冰片敏感的类褪黑素8型瞬时受体电位通道（TRPM8）。在本研究中，我们研究了六种植物大麻素[即CBD、THC、CBD酸、THC酸、大麻色烯（CBC）和大麻萜酚（CBG）]对过表达这两种通道的HEK-293细胞或大鼠背根神经节（DRG）感觉神经元中TRPA1和TRPM8介导的细胞内Ca²⁺增加的影响。所有测试化合物均能在HEK-293细胞中诱导TRPA1介导的Ca²⁺升高，其效力与异硫氰酸芥子油（MO）相当，其中效力最强的是CBC（半数有效浓度EC(50)=60 nM），效力最弱的是CBG和CBD酸（EC(50)=3.4 - 12.0 μM）。CBC也能激活对MO敏感的DRG神经元，不过效力较低（EC(50)=34.3 μM）。此外，尽管测试的化合物均未在HEK-293细胞中激活TRPM8介导的Ca²⁺升高，但除CBC外，它们在薄荷醇或异冰片诱导该反应时均能拮抗此反应。CBD、CBG、THC和THC酸效力相当（半数抑制浓度IC(50)=70 - 160 nM），而CBD酸是效力最弱的化合物（IC(50)=0.9 - 1.6 μM）。CBG在对异冰片敏感的DRG神经元中也能抑制Ca²⁺升高，其效力（IC(50)=4.5 μM）与花生四烯乙醇胺（IC(50)=10 μM）相似。我们的研究结果表明，植物大麻素和大麻提取物也通过与TRPA1和TRPM8通道相互作用发挥其部分药理作用，这对疼痛和癌症的治疗可能具有潜在意义。
