Cannabidiolic Acid Prevents Vomiting in Suncus Murinus and Nausea-Induced Behaviour in Rats by Enhancing 5-HT1A Receptor Activation

Br J Pharmacol. 2013 Mar;168(6):1456-70. doi: 10.1111/bph.12043.

Abstract

Background and purpose: To evaluate the ability of cannabidiolic acid (CBDA) to reduce nausea and vomiting and enhance 5-HT(1A) receptor activation in animal models.

Experimental approach: We investigated the effect of CBDA on (i) lithium chloride (LiCl)-induced conditioned gaping to a flavour (nausea-induced behaviour) or a context (model of anticipatory nausea) in rats; (ii) saccharin palatability in rats; (iii) motion-, LiCl- or cisplatin-induced vomiting in house musk shrews (Suncus murinus); and (iv) rat brainstem 5-HT(1A) receptor activation by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and mouse whole brain CB(1) receptor activation by CP55940, using [³⁵S]GTPγS-binding assays.

Key results: In shrews, CBDA (0.1 and/or 0.5 mg·kg⁻¹ i.p.) reduced toxin- and motion-induced vomiting, and increased the onset latency of the first motion-induced emetic episode. In rats, CBDA (0.01 and 0.1 mg·kg⁻¹ i.p.) suppressed LiCl- and context-induced conditioned gaping, effects that were blocked by the 5-HT(1A) receptor antagonist, WAY100635 (0.1 mg·kg⁻¹ i.p.), and, at 0.01 mg·kg⁻¹ i.p., enhanced saccharin palatability. CBDA-induced suppression of LiCl-induced conditioned gaping was unaffected by the CB₁ receptor antagonist, SR141716A (1 mg·kg⁻¹ i.p.). In vitro, CBDA (0.1-100 nM) increased the E(max) of 8-OH-DPAT.

Conclusions and implications: Compared with cannabidiol, CBDA displays significantly greater potency at inhibiting vomiting in shrews and nausea in rats, and at enhancing 5-HT(1A) receptor activation, an action that accounts for its ability to attenuate conditioned gaping in rats. Consequently, CBDA shows promise as a treatment for nausea and vomiting, including anticipatory nausea for which no specific therapy is currently available.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiemetics / antagonists & inhibitors
  • Antiemetics / therapeutic use*
  • Behavior, Animal / drug effects
  • Brain / drug effects*
  • Brain / metabolism
  • Brain Stem / drug effects
  • Brain Stem / metabolism
  • Cannabinoid Receptor Antagonists / pharmacology
  • Cannabinoids / antagonists & inhibitors
  • Cannabinoids / therapeutic use*
  • Female
  • Male
  • Mice
  • Motion Sickness / physiopathology
  • Motion Sickness / prevention & control
  • Nausea / chemically induced
  • Nausea / etiology
  • Nausea / prevention & control*
  • Nerve Tissue Proteins / agonists
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Serotonin, 5-HT1A / chemistry
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Serotonin 5-HT1 Receptor Agonists / chemistry
  • Serotonin 5-HT1 Receptor Agonists / pharmacology
  • Serotonin 5-HT1 Receptor Agonists / therapeutic use*
  • Serotonin 5-HT1 Receptor Antagonists / pharmacology
  • Shrews
  • Vomiting / chemically induced
  • Vomiting / etiology
  • Vomiting / prevention & control*

Substances

  • Antiemetics
  • Cannabinoid Receptor Antagonists
  • Cannabinoids
  • Nerve Tissue Proteins
  • Receptor, Cannabinoid, CB1
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT1 Receptor Antagonists
  • Receptor, Serotonin, 5-HT1A
  • cannabidiolic acid