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Comparative Study
, 150 (5), 586-94

The Psychoactive Plant Cannabinoid, Delta9-tetrahydrocannabinol, Is Antagonized by Delta8- And Delta9-tetrahydrocannabivarin in Mice in Vivo

Affiliations
Comparative Study

The Psychoactive Plant Cannabinoid, Delta9-tetrahydrocannabinol, Is Antagonized by Delta8- And Delta9-tetrahydrocannabivarin in Mice in Vivo

R G Pertwee et al. Br J Pharmacol.

Abstract

Background and purpose: To follow up in vitro evidence that Delta(9)-tetrahydrocannabivarin extracted from cannabis (eDelta(9)-THCV) is a CB(1) receptor antagonist by establishing whether synthetic Delta(9)-tetrahydrocannabivarin (O-4394) and Delta(8)-tetrahydrocannabivarin (O-4395) behave as CB(1) antagonists in vivo.

Experimental approach: O-4394 and O-4395 were compared with eDelta(9)-THCV as displacers of [(3)H]-CP55940 from specific CB(1) binding sites on mouse brain membranes and as antagonists of CP55940 in [(35)S]GTPgammaS binding assays performed with mouse brain membranes and of R-(+)-WIN55212 in mouse isolated vasa deferentia. Their ability to antagonize in vivo effects of 3 or 10 mg kg(-1) (i.v.) Delta(9)-tetrahydrocannabinol in mice was then investigated.

Key results: O-4394 and O-4395 exhibited similar potencies to eDelta(9)-THCV as displacers of [(3)H]-CP55940 (K (i)=46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [(35)S]GTPgammaS binding assay (apparent K (B)=82.1 and 125.9 nM, respectively) and R-(+)-WIN55212 in the vas deferens (apparent K (B)=4.8 and 3.9 nM respectively). At i.v. doses of 0.1, 0.3, 1.0 and/or 3 mg kg(-1) O-4394 and O-4395 attenuated Delta(9)-tetrahydrocannabinol-induced anti-nociception (tail-flick test) and hypothermia (rectal temperature). O-4395 but not O-4394 also antagonized Delta(9)-tetrahydrocannabinol-induced ring immobility. By themselves, O-4395 and O-4394 induced ring immobility at 3 or 10 mg kg(-1) (i.v.) and antinociception at doses above 10 mg kg(-1) (i.v.). O-4395 also induced hypothermia at 3 mg kg(-1) (i.v.) and above.

Conclusions and implications: O-4394 and O-4395 exhibit similar in vitro potencies to eDelta(9)-THCV as CB(1) receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Delta(9)-tetrahydrocannabinol in vivo.

Figures

Figure 1
Figure 1
Displacement of [3H]-CP55940 by (a) O-4394 and (b) O-4395 from specific binding sites on mouse whole brain membranes. Each symbol represents the mean percent displacement±s.e.m. Mean Ki-values for this displacement have been calculated from these data and these values are listed in Table 1.
Figure 2
Figure 2
The effect of 1 μM O-4394 and O-4395 on the mean log concentration–response curve of CP55940 for stimulation of [35S]GTPγS binding (n=4 or 5; upper panels) and on [35S]GTPγS binding in the absence of CP55940 (n=6; lower panels). Each symbol represents the mean percentage change in [35S]GTPγS binding to mouse whole brain membranes and vertical lines show s.e.m. Mean apparent KB values of O-4394 and O-4395 for their antagonism of CP55940 have been calculated from the data in the upper panels and these values are listed in Table 1. The asterisks in the lower panel denote significant differences from zero (*P<0.05; ***P<0.001; one-sample t-test).
Figure 3
Figure 3
The effect of pretreatment with (a) 100 nM O-4394 or (b) 100 nM O-4395 on the mean log concentration–response curve of R-(+)-WIN55212 in the mouse isolated vas deferens. Each symbol represents the mean value (and vertical lines show s.e.m.) for inhibition of electrically evoked contractions expressed as a percentage of the amplitude of the twitch response measured immediately before the first addition of R-(+)-WIN55212 to the organ bath. O-4394, O-4395 or DMSO was added 30 min before the first addition of R-(+)-WIN55212, further additions of which were made at 15 min intervals. Each log concentration–response curve was constructed cumulatively without washout (n=7). Mean apparent KB values of O-4394 and O-4395 for their antagonism of R-(+)-WIN55212 have been calculated from these data and these values are listed in Table 1.
Figure 4
Figure 4
Effects of O-4394 (n=6 or 12; left-hand panels) and O-4395 (n=12 or 15; right-hand panels) on the ability of Δ9-THC, 10 mg kg−1 i.v., to induce (a) anti-nociception at +20 min, (b) ring immobility at +40 min and (c) hypothermia at +60 min in mice. Each column represents the mean value and vertical lines show s.e.m. O-4394 and O-4395 were injected i.v. immediately before Δ9-THC. %MPE is the percentage of maximum possible effect in the tail-flick test. The symbol # denotes a significantly greater response to Δ9-THC (T) than to its vehicle (V; P<0.001; ANOVA followed by Fisher's PLSD test) and asterisks indicate significant differences between responses to Δ9-THC+vehicle and responses to Δ9-THC+O-4394 or Δ9-THC+O-4395 (*P<0.05; **P<0.01; ***P<0.001; ANOVA followed by Fisher's PLSD test).
Figure 5
Figure 5
Effects of i.v. injections of O-4394 (n=6–10; left-hand panels) and O-4395 (n=6–11; right-hand panels) on (a) anti-nociception at +20 min, (b) ring immobility at +40 min and (c) hypothermia at +60 min in mice. Each column represents the mean value and vertical lines show s.e.m. In some experiments, injection of O-4394 or O-4395 at 56 mg kg−1 i.v. was preceded at −10 min by an i.p. injection of 3 mg kg−1 SR141716A (solid columns). %MPE is the percentage of maximum possible effect in the tail-flick test. Asterisks denote significant differences between the effects of vehicle (V) and O-4394 or O-4395 (*P<0.05; **P<0.01; ***P<0.001; ANOVA followed by Fisher's PLSD test) and the symbol # denotes significant differences between responses to O-4394 or O-4395 alone at 56 mg kg−1 i.v. and responses to this dose of O-4394 or O-4395 following pretreatment with SR141716A (P<0.05; ANOVA followed by Fisher's PLSD test). Mean antinociceptive ED50 values with 95% confidence limits shown in parentheses were 43 mg kg−1 (22 and 83 mg kg−1) for O-4394 and 44 mg kg−1 (23 and 82 mg kg−1) for O-4395.
Figure 6
Figure 6
Effects of i.v. injections of Δ9-THC (T) at 3 mg kg−1 (n=5 or 6) on (a) anti-nociception at +20 min, (b) ring immobility at +40 min and (c) hypothermia at +60 min in mice. Each column represents the mean value and vertical lines show s.e.m. Injection of Δ9-THC was preceded at −10 min by an i.p. injection of either the vehicle (V) or 3 mg kg−1 SR141716A (SR). %MPE is the percentage of maximum possible effect in the tail-flick test. Asterisks denote significant differences between the effects of vehicle and Δ9-THC (*P<0.05; **P<0.01; ANOVA followed by Fisher's PLSD test) and the symbol # denotes significant differences between effects of Δ9-THC following pretreatment with vehicle and its effects following pretreatment with SR141716A (#P<0.05; ##P<0.01; ANOVA followed by Fisher's PLSD test).

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