Evaluation of the potential of the phytocannabinoids, cannabidivarin (CBDV) and Δ(9) -tetrahydrocannabivarin (THCV), to produce CB1 receptor inverse agonism symptoms of nausea in rats

Abstract

Background and purpose: The cannabinoid 1 (CB1 ) receptor inverse agonists/antagonists, rimonabant (SR141716, SR) and AM251, produce nausea and potentiate toxin-induced nausea by inverse agonism (rather than antagonism) of the CB1 receptor. Here, we evaluated two phytocannabinoids, cannabidivarin (CBDV) and Δ(9) -tetrahydrocannabivarin (THCV), for their ability to produce these behavioural effect characteristics of CB1 receptor inverse agonism in rats.

Experimental approach: In experiment 1, we investigated the potential of THCV and CBDV to produce conditioned gaping (measure of nausea-induced behaviour) in the same manner as SR and AM251. In experiment 2, we investigated the potential of THCV and CBDV to enhance conditioned gaping produced by a toxin in the same manner as CB1 receptor inverse agonists.

Key results: SR (10 and 20 mg·kg(-1) ) and AM251 (10 mg·kg(-1) ) produced conditioned gaping; however, THCV (10 or 20 mg·kg(-1) ) and CBDV (10 or 200 mg·kg(-1) ) did not. At a subthreshold dose for producing nausea, SR (2.5 mg·kg(-1) ) enhanced lithium chloride (LiCl)-induced conditioned gaping, whereas Δ(9) -tetrahydrocannabinol (THC, 2.5 and 10 mg·kg(-1) ), THCV (2.5 or 10 mg·kg(-1) ) and CBDV (2.5 or 200 mg·kg(-1) ) did not; in fact, THC (2.5 and 10 mg·kg(-1) ), THCV (10 mg·kg(-1) ) and CBDV (200 mg·kg(-1) ) suppressed LiCl-induced conditioned gaping, suggesting anti-nausea potential.

Conclusions and implications: The pattern of findings indicates that neither THCV nor CBDV produced a behavioural profile characteristic of CB1 receptor inverse agonists. As well, these compounds may have therapeutic potential in reducing nausea.

Keywords: CB1 receptor antagonism; CB1 receptor inverse agonism; THC; anhedonia; cannabidivarin; depression; nausea; rimonabant; tetrahydrocannabivarin.

Figure 1

Mean number (±SEM) of gapes at test elicited by 0.1% saccharin solution previously paired with each compound during the drug-free test trial. Numbers in parentheses indicate n per group. *P < 0.05; ***P < 0.001 from other groups indicated by line [10 mg·kg⁻¹ THCV, 20 mg·kg⁻¹ THCV, 10 mg·kg⁻¹ CBDV, 200 mg·kg⁻¹ CBDV and VEH, which did not differ from one another (ns)]. Those conditioned with 10 mg·kg⁻¹ SR, 20 mg·kg⁻¹ SR and AM251 did not significantly differ from one another, although there was a trend for 20 mg·kg⁻¹ SR to display more gaping than 10 mg·kg⁻¹ SR (P = 0.07).

Figure 2

Mean number (±SEM) of tongue protrusions during conditioning elicited by 0.1% saccharin solution 30 min following pretreatment with VEH, 2.5 mg·kg⁻¹ SR, 2.5 mg·kg⁻¹ THC, 10 mg·kg⁻¹ THC, 2.5 mg·kg⁻¹ CBDV, 200 mg·kg⁻¹ CBDV, 2.5 mg·kg⁻¹ THCV or 10 mg·kg⁻¹ THCV. Both groups pretreated with 2.5 mg·kg⁻¹ SR and 10 mg·kg⁻¹ THCV displayed suppressed (**P < 0.02) hedonic reactions relative to VEH-pretreated controls.

Figure 3

Mean number (±SEM) of gapes elicited by 0.1% saccharin solution previously paired with LiCl during the drug-free TR test trial. Only those pretreated with SR displayed potentiated gaping (**P < 0.025 relative to VEH-pretreated controls) during the drug-free test, suggesting that pretreatment during conditioning enhanced the nausea produced by LiCl. In contrast, 10 mg·kg⁻¹ THCV completely eliminated LiCl-induced gaping (***P < 0.001 relative to VEH) and 200 mg·kg⁻¹ CBDV, 2.5 mg·kg⁻¹ THC (*P < 0.05 relative to VEH) and 10 mg·kg⁻¹ THC (**P < 0.01), reduced LiCl-induced gaping during the drug-free test trial, suggesting that pretreatment during conditioning eliminated the nausea produced by LiCl.