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.
Yang
Keun-Hang
KH
Department of Biological Sciences, Schmid College of Science, Chapman University, Orange, California, USA.
Galadari
Sehamuddin
S
Isaev
Dmytro
D
Petroianu
Georg
G
Shippenberg
Toni S
TS
Oz
Murat
M
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