Direct inhibition by cannabinoids of human 5-HT3A receptors: probable involvement of an allosteric modulatory site M. Barann1,2, G. Molderings1, M. Brüss1, H. Bönisch1, B. W. Urban2 and M. Göthert1 1 Institut für Pharmakologie und Toxikologie, Universität Bonn, Reuterstraße 2b, D-53113 Bonn, Germany 2 Klinik für Anästhesiologie und spezielle Intensivmedizin, Universitätskliniken Bonn, Sigmund-Freud-Straße 25, D-53105 Bonn, Germany Correspondence to: M. Göthert, E-mail: goethert@uni-bonn.de 1 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. 2 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. 3 WIN55,212-2 did not change the EC50 value of 5-HT in stimulating current, but reduced the maximum effect. 4 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. 5 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. British Journal of Pharmacology (2002) 137, 589–596. Abbreviations: Anandamide, ((all Z)-N-(2-hydroxyethyl)-5,8,11,14-eicosa-tetraenamide); CP55940, (-)-cis -3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol; GR65630, (3-5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3-yl)-1-propanone); JWH-015, ([2-methyl-1-propyl-1H-indol-3-yl]-1-naphthalen-ylmethanone); 5-HT, 5-hydroxytryptamine creatinine sulphate; SR141716A, (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbox-amide hydrochloride); 9THC, 9-tetrahydrocannabinol; WIN55,212-2, ((R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo [1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone) mesyalte; WIN55,212-3, ((S)-(-)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxaxin-6-yl]-1-naphthalenylmethanone) mesylate Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.