Abstract
The effect of the plant-derived nonpsychotropic cannabinoid, cannabidiol (CBD), on the function of hydroxytryptamine (5-HT)3A receptors expressed in Xenopus laevis oocytes was investigated using two-electrode voltage-clamp techniques. CBD reversibly inhibited 5-HT (1 μM)-evoked currents in a concentration-dependent manner (IC50 = 0.6 μM). CBD (1 μM) did not alter specific binding of the 5-HT3A antagonist [3H]3-(5-methyl-1H-imidazol-4-yl)-1-(1-methylindol-3-yl)propan-1-one (GR65630), in oocytes expressing 5-HT3A receptors. In the presence of 1 μM CBD, the maximal 5-HT-induced currents were also inhibited. The EC50 values were 1.2 and 1.4 μM, in the absence and presence of CBD, indicating that CBD acts as a noncompetitive antagonist of 5-HT3 receptors. Neither intracellular BAPTA injection nor pertussis toxin pretreatment (5 μg/ml) altered the CBD-evoked inhibition of 5-HT-induced currents. CBD inhibition was inversely correlated with 5-HT3A expression levels and mean 5-HT3 receptor current density. Pretreatment with actinomycin D, which inhibits protein transcription, decreased the mean 5-HT3 receptor current density and increased the magnitude of CBD inhibition. These data demonstrate that CBD is an allosteric inhibitor of 5-HT3 receptors expressed in X. laevis oocytes. They further suggest that allosteric inhibition of 5-HT3 receptors by CBD may contribute to its physiological roles in the modulation of nociception and emesis.
Footnotes
This work was supported in part by the Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse and from the Faculty of Medicine and Health Science, United Arab Emirates University.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.162594.
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ABBREVIATIONS:
- 5-HT
- 5-hydroxytryptamine
- THC
- tetrahydrocannabinol
- CB
- cannabinoid
- CBD
- cannabidiol
- WIN55,212-2
- 4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one
- CP55,940
- (1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol
- JWH-015
- 1-propyl-2-methyl-3-(1-naphthoyl)indole
- cRNA
- complementary RNA
- Icap
- capacitive current
- Cm
- membrane capacitance
- PTX
- pertussis toxin
- BAPTA
- 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
- ActD
- actinomycin D
- MDL72222
- tropanyl 3,5-dichlorobenzoate
- HB
- homogenization buffer
- GR65630
- 3-(5-methyl-1H-imidazol-4-yl)-1-(1-methylindol-3-yl)propan-1-one
- ANOVA
- analysis of variance
- SR-141716A
- N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride.
- Received October 9, 2009.
- Accepted January 14, 2010.
- U.S. Government work not protected by U.S. copyright
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