Direct inhibition by cannabinoids of human 5-HT3A receptors: probable involvement of an allosteric modulatory site

Br J Pharmacol. 2002 Nov;137(5):589-96. doi: 10.1038/sj.bjp.0704829.


Excised outside-out patches from HEK293 cells stably transfected with the human (h) 5-HT3A receptor cDNA were used to determine the effects of cannabinoid receptor ligands on the 5-HT-induced current using the patch clamp technique. In addition, binding studies with radioligands for 5-HT3 as well as for cannabinoid CB1 and CB2 receptors were carried out. The 5-HT-induced current was inhibited by the following cannabinoid receptor agonists (at decreasing order of potency): 9-THC, WIN55,212-2, anandamide, JWH-015 and CP55940. The WIN55,212-2-induced inhibition was not altered by SR141716A, a CB1 receptor antagonist. WIN55,212-3, an enantiomer of WIN55,212-2, did not affect the 5-HT-induced current. WIN55,212-2 did not change the EC50 value of 5-HT in stimulating current, but reduced the maximum effect. The CB1 receptor ligand [3H]-SR141716A and the CB1/CB2 receptor ligand [3H]-CP55940 did not specifically bind to parental HEK293 cells. In competition experiments on membranes of HEK293 cells transfected with the h5-HT3A receptor cDNA, WIN55,212-2, CP55940, anandamide and SR141716A did not affect [3H]-GR65630 binding, but 5-HT caused a concentration dependent-inhibition. In conclusion, cannabinoids stereoselectively inhibit currents through recombinant h5-HT3A receptors independently of cannabinoid receptors. Probably the cannabinoids act allosterically at a modulatory site of the h5-HT3A receptor. Thus the functional state of the receptor can be controlled by the endogenous ligand anandamide. This site is a potential target for new analgesic and antiemetic drugs.

MeSH terms

  • Allosteric Site / drug effects*
  • Allosteric Site / physiology
  • Cannabinoids / pharmacology*
  • Cell Line
  • Dose-Response Relationship, Drug
  • Humans
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Radioligand Assay
  • Receptors, Cannabinoid
  • Receptors, Drug / agonists
  • Receptors, Drug / metabolism
  • Receptors, Serotonin / genetics
  • Receptors, Serotonin / metabolism*
  • Receptors, Serotonin, 5-HT3
  • Selective Serotonin Reuptake Inhibitors / pharmacology*
  • Serotonin / metabolism*
  • Serotonin / pharmacology


  • Cannabinoids
  • Receptors, Cannabinoid
  • Receptors, Drug
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • Serotonin Uptake Inhibitors
  • Serotonin