The nonpsychoactive cannabinoid cannabidiol inhibits 5-hydroxytryptamine3A receptor-mediated currents in Xenopus laevis oocytes.
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 microM)-evoked currents in a concentration-dependent manner (IC50 = 0.6 microM). CBD (1 microM) 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 microM CBD, the maximal 5-HT-induced currents were also inhibited. The EC50 values were 1.2 and 1.4 microM, 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 microg/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.
Department of Biological Sciences, Schmid College of Science, Chapman University, Orange, California, USA.
Keun-Hang
KH
Yang
Sehamuddin
S
Galadari
Dmytro
D
Isaev
Georg
G
Petroianu
Toni S
TS
Shippenberg
Murat
M
Oz
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002185:Cannabidiol / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D009865:Oocytes / Q000187:drug effects* / Q000502:physiology; D037342:Pertussis Toxin / Q000494:pharmacology; D044406:Receptors, Serotonin, 5-HT3 / Q000096:biosynthesis / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D058831:Serotonin 5-HT3 Receptor Antagonists; D015398:Signal Transduction / Q000187:drug effects; D014982:Xenopus laevis
D007093:Imidazoles; D007211:Indoles; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; C059068:GR 65630; D002185:Cannabidiol; D012701:Serotonin; D004533:Egtazic Acid; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid