Evidence that the plant cannabinoid cannabigerol is a highly potent α2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist

Maria Grazia Cascio, Lisa Anne Gauson, Lesley Ann Stevenson, Ruth Alexandra Ross, Roger Guy Pertwee

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Background and purpose: 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.

Experimental approach: The [S-35]GTP gamma S 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 [H-3]CP55940 from mouse CB1 and human CB2 cannabinoid receptors and to inhibit electrically evoked contractions of the mouse isolated vas deferens was also investigated.

Key results: In the brain membrane experiments, cannabigerol behaved as a potent alpha(2)-adrenoceptor agonist (EC50 = 0.2 nM) and antagonized the 5-HT1A receptor agonist, R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (apparent K-B = 51.9 nM). At 10 mu M, it also behaved as a CB1 receptor competitive antagonist. Additionally, cannabigerol inhibited evoked contractions of the vas deferens in a manner that appeared to be alpha(2)-adrenoceptor-mediated (EC50 = 72.8 nM) and displayed significant affinity for mouse CB1 and human CB2 receptors.

Conclusions and implications: This investigation has provided the first evidence that cannabigerol can activate alpha(2)-adrenoceptors, bind to cannabinoid CB1 and CB2 receptors and block CB1 and 5-HT1A receptors. It will now be important to investigate why cannabigerol produced signs of agonism more potently in the [S-35]GTP gamma S binding assay than in the vas deferens and also whether it can inhibit noradrenaline uptake in this isolated tissue and in the brain. British Journal of Pharmacology (2010) 159, 129-141; doi:10.1111/j.1476-5381.2009.00515.x; published online 4 December 2009

Original languageEnglish
Pages (from-to)129-141
Number of pages13
JournalBritish Journal of Pharmacology
Volume159
Issue number1
Early online date4 Dec 2009
DOIs
Publication statusPublished - Jan 2010

Keywords

  • cannabigerol
  • CP55940
  • mouse vas deferens
  • alpha(2)-adrenoceptor
  • 5-HT1A receptor
  • CB1 receptor
  • clonidine
  • dexmedetomidine
  • maprotiline
  • R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin
  • mouse vas-deferens
  • pharmacological profile
  • CB1
  • noradrenaline
  • hashish
  • release
  • Delta(9)-tetrahydrocannabivarin
  • adrenoceptors
  • constituents
  • cannabidiol
  • cannabigerol
  • CP55940
  • mouse vas deferens
  • a2-adrenoceptor
  • 5-HT1A receptor
  • CB1 receptor
  • clonidine
  • maprotiline

Cite this

Evidence that the plant cannabinoid cannabigerol is a highly potent α2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. / Cascio, Maria Grazia; Gauson, Lisa Anne; Stevenson, Lesley Ann; Ross, Ruth Alexandra; Pertwee, Roger Guy.

In: British Journal of Pharmacology, Vol. 159, No. 1, 01.2010, p. 129-141.

Research output: Contribution to journalArticle

Cascio, Maria Grazia ; Gauson, Lisa Anne ; Stevenson, Lesley Ann ; Ross, Ruth Alexandra ; Pertwee, Roger Guy. / Evidence that the plant cannabinoid cannabigerol is a highly potent α2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. In: British Journal of Pharmacology. 2010 ; Vol. 159, No. 1. pp. 129-141.
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N2 - Background and purpose: 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.Experimental approach: The [S-35]GTP gamma S 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 [H-3]CP55940 from mouse CB1 and human CB2 cannabinoid receptors and to inhibit electrically evoked contractions of the mouse isolated vas deferens was also investigated.Key results: In the brain membrane experiments, cannabigerol behaved as a potent alpha(2)-adrenoceptor agonist (EC50 = 0.2 nM) and antagonized the 5-HT1A receptor agonist, R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (apparent K-B = 51.9 nM). At 10 mu M, it also behaved as a CB1 receptor competitive antagonist. Additionally, cannabigerol inhibited evoked contractions of the vas deferens in a manner that appeared to be alpha(2)-adrenoceptor-mediated (EC50 = 72.8 nM) and displayed significant affinity for mouse CB1 and human CB2 receptors.Conclusions and implications: This investigation has provided the first evidence that cannabigerol can activate alpha(2)-adrenoceptors, bind to cannabinoid CB1 and CB2 receptors and block CB1 and 5-HT1A receptors. It will now be important to investigate why cannabigerol produced signs of agonism more potently in the [S-35]GTP gamma S binding assay than in the vas deferens and also whether it can inhibit noradrenaline uptake in this isolated tissue and in the brain. British Journal of Pharmacology (2010) 159, 129-141; doi:10.1111/j.1476-5381.2009.00515.x; published online 4 December 2009

AB - Background and purpose: 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.Experimental approach: The [S-35]GTP gamma S 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 [H-3]CP55940 from mouse CB1 and human CB2 cannabinoid receptors and to inhibit electrically evoked contractions of the mouse isolated vas deferens was also investigated.Key results: In the brain membrane experiments, cannabigerol behaved as a potent alpha(2)-adrenoceptor agonist (EC50 = 0.2 nM) and antagonized the 5-HT1A receptor agonist, R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (apparent K-B = 51.9 nM). At 10 mu M, it also behaved as a CB1 receptor competitive antagonist. Additionally, cannabigerol inhibited evoked contractions of the vas deferens in a manner that appeared to be alpha(2)-adrenoceptor-mediated (EC50 = 72.8 nM) and displayed significant affinity for mouse CB1 and human CB2 receptors.Conclusions and implications: This investigation has provided the first evidence that cannabigerol can activate alpha(2)-adrenoceptors, bind to cannabinoid CB1 and CB2 receptors and block CB1 and 5-HT1A receptors. It will now be important to investigate why cannabigerol produced signs of agonism more potently in the [S-35]GTP gamma S binding assay than in the vas deferens and also whether it can inhibit noradrenaline uptake in this isolated tissue and in the brain. British Journal of Pharmacology (2010) 159, 129-141; doi:10.1111/j.1476-5381.2009.00515.x; published online 4 December 2009

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KW - maprotiline

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KW - hashish

KW - release

KW - Delta(9)-tetrahydrocannabivarin

KW - adrenoceptors

KW - constituents

KW - cannabidiol

KW - cannabigerol

KW - CP55940

KW - mouse vas deferens

KW - a2-adrenoceptor

KW - 5-HT1A receptor

KW - CB1 receptor

KW - clonidine

KW - maprotiline

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