Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT1A somatodendritic autoreceptors in the dorsal raphe nucleus

E. M. Rock, D. Bolognini, C. L. Limebeer, M. G. Cascio, S. Anavi-Goffer, P. J. Fletcher, R. Mechoulam, R. G. Pertwee, L. A. Parker

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE

To evaluate the hypothesis that activation of somatodendritic 5-HT1A autoreceptors in the dorsal raphe nucleus (DRN) produces the anti-emetic/anti-nausea effects of cannabidiol (CBD), a primary non-psychoactive cannabinoid found in cannabis.

EXPERIMENTAL APPROACH

The potential of systemic and intra-DRN administration of 5-HT1A receptor antagonists, WAY100135 or WAY100635, to prevent the anti-emetic effect of CBD in shrews (Suncus murinus) and the anti-nausea-like effects of CBD (conditioned gaping) in rats were evaluated. Also, the ability of intra-DRN administration of CBD to produce anti-nausea-like effects (and reversal by systemic WAY100635) was assessed. In vitro studies evaluated the potential of CBD to directly target 5-HT1A receptors and to modify the ability of the 5-HT1A agonist, 8-OH-DPAT, to stimulate [S-35]GTP gamma S binding in rat brainstem membranes.

KEY RESULTS

CBD suppressed nicotine-, lithium chloride (LiCl)- and cisplatin (20 mg.kg(-1), but not 40 mg.kg(-1))-induced vomiting in the S. murinus and LiCl-induced conditioned gaping in rats. Anti-emetic and anti-nausea-like effects of CBD were suppressed by WAY100135 and the latter by WAY100635. When administered to the DRN: (i) WAY100635 reversed anti-nausea-like effects of systemic CBD, and (ii) CBD suppressed nausea-like effects, an effect that was reversed by systemic WAY100635. CBD also displayed significant potency (in a bell-shaped dose-response curve) at enhancing the ability of 8-OH-DPAT to stimulate [35S] GTPgS binding to rat brainstem membranes in vitro. Systemically administered CBD and 8-OH-DPAT synergistically suppressed LiCl-induced conditioned gaping.

CONCLUSIONS AND IMPLICATIONS

These results suggest that CBD produced its anti-emetic/anti-nausea effects by indirect activation of the somatodendritic 5-HT1A autoreceptors in the DRN.

Original languageEnglish
Pages (from-to)2620-2634
Number of pages15
JournalBritish Journal of Pharmacology
Volume165
Issue number8
Early online date23 Mar 2012
DOIs
Publication statusPublished - Apr 2012

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Cannabidiol
Autoreceptors
Cannabis
Nausea
Vomiting
Antiemetics
Lithium Chloride
8-Hydroxy-2-(di-n-propylamino)tetralin
Receptor, Serotonin, 5-HT1A
Aptitude
Brain Stem
Dorsal Raphe Nucleus
Serotonin 5-HT1 Receptor Antagonists
Shrews
Serotonin 5-HT1 Receptor Agonists
Guanosine 5'-O-(3-Thiotriphosphate)
Membranes
Cannabinoids
Nicotine
Cisplatin

Keywords

  • cannabidiol
  • 5-HT1A
  • endocannabinoid
  • nausea
  • vomiting
  • shrew
  • rat
  • taste reactivity
  • gaping
  • conditioned disgust
  • emesis
  • conditioned rejection reactions
  • cisplatin-inuced emesis
  • motion-induced emesis
  • house musk shrew
  • taste avoidance
  • suncus-murinus
  • CB1 receptors
  • constituent cannabidiol
  • allosteric modulation
  • disgust reactions

Cite this

Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT1A somatodendritic autoreceptors in the dorsal raphe nucleus. / Rock, E. M.; Bolognini, D.; Limebeer, C. L.; Cascio, M. G.; Anavi-Goffer, S.; Fletcher, P. J.; Mechoulam, R.; Pertwee, R. G.; Parker, L. A.

In: British Journal of Pharmacology, Vol. 165, No. 8, 04.2012, p. 2620-2634.

Research output: Contribution to journalArticle

Rock, E. M. ; Bolognini, D. ; Limebeer, C. L. ; Cascio, M. G. ; Anavi-Goffer, S. ; Fletcher, P. J. ; Mechoulam, R. ; Pertwee, R. G. ; Parker, L. A. / Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT1A somatodendritic autoreceptors in the dorsal raphe nucleus. In: British Journal of Pharmacology. 2012 ; Vol. 165, No. 8. pp. 2620-2634.
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abstract = "BACKGROUND AND PURPOSETo evaluate the hypothesis that activation of somatodendritic 5-HT1A autoreceptors in the dorsal raphe nucleus (DRN) produces the anti-emetic/anti-nausea effects of cannabidiol (CBD), a primary non-psychoactive cannabinoid found in cannabis.EXPERIMENTAL APPROACHThe potential of systemic and intra-DRN administration of 5-HT1A receptor antagonists, WAY100135 or WAY100635, to prevent the anti-emetic effect of CBD in shrews (Suncus murinus) and the anti-nausea-like effects of CBD (conditioned gaping) in rats were evaluated. Also, the ability of intra-DRN administration of CBD to produce anti-nausea-like effects (and reversal by systemic WAY100635) was assessed. In vitro studies evaluated the potential of CBD to directly target 5-HT1A receptors and to modify the ability of the 5-HT1A agonist, 8-OH-DPAT, to stimulate [S-35]GTP gamma S binding in rat brainstem membranes.KEY RESULTSCBD suppressed nicotine-, lithium chloride (LiCl)- and cisplatin (20 mg.kg(-1), but not 40 mg.kg(-1))-induced vomiting in the S. murinus and LiCl-induced conditioned gaping in rats. Anti-emetic and anti-nausea-like effects of CBD were suppressed by WAY100135 and the latter by WAY100635. When administered to the DRN: (i) WAY100635 reversed anti-nausea-like effects of systemic CBD, and (ii) CBD suppressed nausea-like effects, an effect that was reversed by systemic WAY100635. CBD also displayed significant potency (in a bell-shaped dose-response curve) at enhancing the ability of 8-OH-DPAT to stimulate [35S] GTPgS binding to rat brainstem membranes in vitro. Systemically administered CBD and 8-OH-DPAT synergistically suppressed LiCl-induced conditioned gaping.CONCLUSIONS AND IMPLICATIONSThese results suggest that CBD produced its anti-emetic/anti-nausea effects by indirect activation of the somatodendritic 5-HT1A autoreceptors in the DRN.",
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TY - JOUR

T1 - Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT1A somatodendritic autoreceptors in the dorsal raphe nucleus

AU - Rock, E. M.

AU - Bolognini, D.

AU - Limebeer, C. L.

AU - Cascio, M. G.

AU - Anavi-Goffer, S.

AU - Fletcher, P. J.

AU - Mechoulam, R.

AU - Pertwee, R. G.

AU - Parker, L. A.

N1 - © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

PY - 2012/4

Y1 - 2012/4

N2 - BACKGROUND AND PURPOSETo evaluate the hypothesis that activation of somatodendritic 5-HT1A autoreceptors in the dorsal raphe nucleus (DRN) produces the anti-emetic/anti-nausea effects of cannabidiol (CBD), a primary non-psychoactive cannabinoid found in cannabis.EXPERIMENTAL APPROACHThe potential of systemic and intra-DRN administration of 5-HT1A receptor antagonists, WAY100135 or WAY100635, to prevent the anti-emetic effect of CBD in shrews (Suncus murinus) and the anti-nausea-like effects of CBD (conditioned gaping) in rats were evaluated. Also, the ability of intra-DRN administration of CBD to produce anti-nausea-like effects (and reversal by systemic WAY100635) was assessed. In vitro studies evaluated the potential of CBD to directly target 5-HT1A receptors and to modify the ability of the 5-HT1A agonist, 8-OH-DPAT, to stimulate [S-35]GTP gamma S binding in rat brainstem membranes.KEY RESULTSCBD suppressed nicotine-, lithium chloride (LiCl)- and cisplatin (20 mg.kg(-1), but not 40 mg.kg(-1))-induced vomiting in the S. murinus and LiCl-induced conditioned gaping in rats. Anti-emetic and anti-nausea-like effects of CBD were suppressed by WAY100135 and the latter by WAY100635. When administered to the DRN: (i) WAY100635 reversed anti-nausea-like effects of systemic CBD, and (ii) CBD suppressed nausea-like effects, an effect that was reversed by systemic WAY100635. CBD also displayed significant potency (in a bell-shaped dose-response curve) at enhancing the ability of 8-OH-DPAT to stimulate [35S] GTPgS binding to rat brainstem membranes in vitro. Systemically administered CBD and 8-OH-DPAT synergistically suppressed LiCl-induced conditioned gaping.CONCLUSIONS AND IMPLICATIONSThese results suggest that CBD produced its anti-emetic/anti-nausea effects by indirect activation of the somatodendritic 5-HT1A autoreceptors in the DRN.

AB - BACKGROUND AND PURPOSETo evaluate the hypothesis that activation of somatodendritic 5-HT1A autoreceptors in the dorsal raphe nucleus (DRN) produces the anti-emetic/anti-nausea effects of cannabidiol (CBD), a primary non-psychoactive cannabinoid found in cannabis.EXPERIMENTAL APPROACHThe potential of systemic and intra-DRN administration of 5-HT1A receptor antagonists, WAY100135 or WAY100635, to prevent the anti-emetic effect of CBD in shrews (Suncus murinus) and the anti-nausea-like effects of CBD (conditioned gaping) in rats were evaluated. Also, the ability of intra-DRN administration of CBD to produce anti-nausea-like effects (and reversal by systemic WAY100635) was assessed. In vitro studies evaluated the potential of CBD to directly target 5-HT1A receptors and to modify the ability of the 5-HT1A agonist, 8-OH-DPAT, to stimulate [S-35]GTP gamma S binding in rat brainstem membranes.KEY RESULTSCBD suppressed nicotine-, lithium chloride (LiCl)- and cisplatin (20 mg.kg(-1), but not 40 mg.kg(-1))-induced vomiting in the S. murinus and LiCl-induced conditioned gaping in rats. Anti-emetic and anti-nausea-like effects of CBD were suppressed by WAY100135 and the latter by WAY100635. When administered to the DRN: (i) WAY100635 reversed anti-nausea-like effects of systemic CBD, and (ii) CBD suppressed nausea-like effects, an effect that was reversed by systemic WAY100635. CBD also displayed significant potency (in a bell-shaped dose-response curve) at enhancing the ability of 8-OH-DPAT to stimulate [35S] GTPgS binding to rat brainstem membranes in vitro. Systemically administered CBD and 8-OH-DPAT synergistically suppressed LiCl-induced conditioned gaping.CONCLUSIONS AND IMPLICATIONSThese results suggest that CBD produced its anti-emetic/anti-nausea effects by indirect activation of the somatodendritic 5-HT1A autoreceptors in the DRN.

KW - cannabidiol

KW - 5-HT1A

KW - endocannabinoid

KW - nausea

KW - vomiting

KW - shrew

KW - rat

KW - taste reactivity

KW - gaping

KW - conditioned disgust

KW - emesis

KW - conditioned rejection reactions

KW - cisplatin-inuced emesis

KW - motion-induced emesis

KW - house musk shrew

KW - taste avoidance

KW - suncus-murinus

KW - CB1 receptors

KW - constituent cannabidiol

KW - allosteric modulation

KW - disgust reactions

U2 - 10.1111/j.1476-5381.2011.01621.x

DO - 10.1111/j.1476-5381.2011.01621.x

M3 - Article

VL - 165

SP - 2620

EP - 2634

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 8

ER -