Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist.
OBJECTIVE
Cannabis is the source of at least seventy phytocannabinoids. The pharmacology of most of these has been little investigated, three notable exceptions being Delta(9)-tetrahydrocannabinol, cannabidiol and Delta(9)-tetrahydrocannabivarin. This investigation addressed the question of whether the little-studied phytocannabinoid, cannabigerol, can activate or block any G protein-coupled receptor.


METHODS
The [(35)S]GTPgammaS binding assay, performed with mouse brain membranes, was used to test the ability of cannabigerol to produce G protein-coupled receptor activation or blockade. Its ability to displace [(3)H]CP55940 from mouse CB(1) and human CB(2) cannabinoid receptors and to inhibit electrically evoked contractions of the mouse isolated vas deferens was also investigated.


RESULTS
In the brain membrane experiments, cannabigerol behaved as a potent alpha(2)-adrenoceptor agonist (EC(50)= 0.2 nM) and antagonized the 5-HT(1A) receptor agonist, R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (apparent K(B)= 51.9 nM). At 10 microM, it also behaved as a CB(1) receptor competitive antagonist. Additionally, cannabigerol inhibited evoked contractions of the vas deferens in a manner that appeared to be alpha(2)-adrenoceptor-mediated (EC(50)= 72.8 nM) and displayed significant affinity for mouse CB(1) and human CB(2) receptors.


CONCLUSIONS
This investigation has provided the first evidence that cannabigerol can activate alpha(2)-adrenoceptors, bind to cannabinoid CB(1) and CB(2) receptors and block CB(1) and 5-HT(1A) receptors. It will now be important to investigate why cannabigerol produced signs of agonism more potently in the [(35)S]GTPgammaS binding assay than in the vas deferens and also whether it can inhibit noradrenaline uptake in this isolated tissue and in the brain.
Cascio
M G
MG
School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.
Gauson
L A
LA
Stevenson
L A
LA
Ross
R A
RA
Pertwee
R G
RG
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002186:Cannabinoids / Q000008:administration & dosage / Q000494:pharmacology*; D002188:Cannabis / Q000737:chemistry; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D011485:Protein Binding; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D002186:Cannabinoids; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; C037036:cannabigerol