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

doi:10.1111/j.1476-5381.2011.01621.x

Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT_1A 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 journal › Article › peer-review

187 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 language	English
Pages (from-to)	2620-2634
Number of pages	15
Journal	British Journal of Pharmacology
Volume	165
Issue number	8
Early online date	23 Mar 2012
DOIs	https://doi.org/10.1111/j.1476-5381.2011.01621.x
Publication status	Published - Apr 2012

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

Access to Document

10.1111/j.1476-5381.2011.01621.x

Cite this

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. (2012). Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT_1A somatodendritic autoreceptors in the dorsal raphe nucleus. British Journal of Pharmacology, 165(8), 2620-2634. https://doi.org/10.1111/j.1476-5381.2011.01621.x

Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT_1A somatodendritic autoreceptors in the dorsal raphe nucleus. / Rock, E. M.; Bolognini, D.; Limebeer, C. L. et al.

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

Research output: Contribution to journal › Article › peer-review

Rock, EM, Bolognini, D, Limebeer, CL, Cascio, MG , Anavi-Goffer, S, Fletcher, PJ, Mechoulam, R, Pertwee, RG & Parker, LA 2012, 'Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT_1A somatodendritic autoreceptors in the dorsal raphe nucleus', British Journal of Pharmacology, vol. 165, no. 8, pp. 2620-2634. https://doi.org/10.1111/j.1476-5381.2011.01621.x

Rock EM, Bolognini D, Limebeer CL, Cascio MG , Anavi-Goffer S, Fletcher PJ et al. Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT_1A somatodendritic autoreceptors in the dorsal raphe nucleus. British Journal of Pharmacology. 2012 Apr;165(8):2620-2634. Epub 2012 Mar 23. doi: 10.1111/j.1476-5381.2011.01621.x

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title = "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",

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.",

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",

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

note = "{\textcopyright} 2011 The Authors. British Journal of Pharmacology {\textcopyright} 2011 The British Pharmacological Society.",

year = "2012",

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doi = "10.1111/j.1476-5381.2011.01621.x",

language = "English",

volume = "165",

pages = "2620--2634",

journal = "British Journal of Pharmacology",

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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.

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

C2 - 21827451

VL - 165

SP - 2620

EP - 2634

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 8