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. 2010 Jun;160(3):677-87.
doi: 10.1111/j.1476-5381.2010.00756.x.

The Plant Cannabinoid Delta9-tetrahydrocannabivarin Can Decrease Signs of Inflammation and Inflammatory Pain in Mice

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Free PMC article

The Plant Cannabinoid Delta9-tetrahydrocannabivarin Can Decrease Signs of Inflammation and Inflammatory Pain in Mice

Daniele Bolognini et al. Br J Pharmacol. .
Free PMC article

Abstract

Background and purpose: The phytocannabinoid, Delta(9)-tetrahydrocannabivarin (THCV), can block cannabinoid CB(1) receptors. This investigation explored its ability to activate CB(2) receptors, there being evidence that combined CB(2) activation/CB(1) blockade would ameliorate certain disorders.

Experimental approach: We tested the ability of THCV to activate CB(2) receptors by determining whether: (i) it inhibited forskolin-stimulated cyclic AMP production by Chinese hamster ovary (CHO) cells transfected with human CB(2) (hCB(2)) receptors; (ii) it stimulated [(35)S]GTPgammaS binding to hCB(2) CHO cell and mouse spleen membranes; (iii) it attenuated signs of inflammation/hyperalgesia induced in mouse hind paws by intraplantar injection of carrageenan or formalin; and (iv) any such anti-inflammatory or anti-hyperalgesic effects were blocked by a CB(1) or CB(2) receptor antagonist.

Key results: THCV inhibited cyclic AMP production by hCB(2) CHO cells (EC(50)= 38 nM), but not by hCB(1) or untransfected CHO cells or by hCB(2) CHO cells pre-incubated with pertussis toxin (100 ng.mL(-1)) and stimulated [(35)S]GTPgammaS binding to hCB(2) CHO and mouse spleen membranes. THCV (0.3 or 1 mg.kg(-1) i.p.) decreased carrageenan-induced oedema in a manner that seemed to be CB(2) receptor-mediated and suppressed carrageenan-induced hyperalgesia. THCV (i.p.) also decreased pain behaviour in phase 2 of the formalin test at 1 mg.kg(-1), and in both phases of this test at 5 mg.kg(-1); these effects of THCV appeared to be CB(1) and CB(2) receptor mediated.

Conclusions and implications: THCV can activate CB(2) receptors in vitro and decrease signs of inflammation and inflammatory pain in mice partly via CB(1) and/or CB(2) receptor activation.

Figures

Figure 1
Figure 1
The structure of THCV.
Figure 2
Figure 2
The effect of THCV and CP55940 on forskolin-induced stimulation of cyclic AMP production in CHO cells transfected with hCB2 receptors that had or had not been pre-incubated overnight with pertussis toxin (PTX; 100 ng·mL−1) (n= 4). EC50 values determined in cells not pre-incubated with pertussis toxin, with 95% CIs shown in brackets, were 38 nM (12 and 124 nM) for THCV and 6.9 nM (3.5 and 13 nM) for CP55940. The corresponding Emax values were 40% (32 and 48%) and 55% (50 and 60%) respectively. Symbols represent mean values ± SEM.
Figure 3
Figure 3
The effect of THCV and CP55940 on forskolin-induced stimulation of cyclic AMP production in CHO cells transfected with hCB1 receptors that (A) had not been or (B) had been pre-incubated overnight with pertussis toxin (PTX; 100 ng·mL−1) (n= 4). The mean Emax value of THCV in (A), with 95% CIs shown in brackets, was −29.6% (16.8 and 42.4%). The mean Emax value of THCV (8.8%) in (B) did not differ significantly from zero. Its 95% CIs were −0.8 and 18.5%. Symbols represent mean values ± SEM.
Figure 5
Figure 5
Effect of THCV (0.3 mg·kg−1 i.p.), administered 30 min before carrageenan (2%, 20 µL intraplantar), on (A) oedema and (B) thermal hypersensitivity evaluated at different times after carrageenan. Data represent mean values ± SEM (n= 5). ***P < 0.001 versus mice treated with vehicle/vehicle. °°P < 0.01, °°°P < 0.001 versus mice treated with vehicle/carrageenan.
Figure 4
Figure 4
Effect of THCV, administered i.p. 30 min before carrageenan (2%, 20 µL intraplantar), on (A) oedema evaluated 2 h after carrageenan, and (B) thermal hypersensitivity, evaluated 3 h after carrageenan. The basal hind paw withdrawal latency displayed by vehicle-treated mice was 10 ± 0.45 s. Data represent mean values ± SEM (n= 9). °°P < 0.01, °°°P < 0.001 versus mice treated with vehicle/carrageenan.
Figure 6
Figure 6
Effect of rimonabant (RIM; 0.5 mg·kg−1 i.p.) and SR144528 (1 mg·kg−1 i.p.) on (A) anti-oedema and (B) anti-nociceptive effects evoked by THCV (0.3 mg·kg−1 i.p.). Antagonists were administered 15 min before THCV, and behavioural evaluations were made 2 h (oedema) and 3 h (thermal hypersensitivity), after carrageenan. Data represent mean values ± SEM (n= 8–10). °°P < 0.01, °°°P < 0.001 versus mice treated with vehicle/carrageenan. $$$P < 0.001 versus mice treated with vehicle/THCV/carrageenan.
Figure 7
Figure 7
Effect of THCV (0.3 mg·kg−1 i.p.), administered after carrageenan once daily for 4 days, on (A) oedema and (B) thermal hypersensitivity. Data represent mean ± SEM (n= 6–8). °°°P < 0.001 versus mice treated with carrageenan/vehicle.
Figure 8
Figure 8
Effect on nociceptive behaviour evoked by formalin (1.25%, 30 µL s.c.) of THCV when administered at different doses by itself (A) or at 5 mg·kg−1 (B) or 1 mg·kg−1 (C) in combination with SR144528 (1 mg·kg−1 i.p.) or rimonabant (0.5 mg·kg−1 i.p.). THCV was administered intraperitoneally 15 min before formalin. Antagonists were given 15 min prior to THCV. Data represent mean values ± SEM (n= 8). °P < 0.05 versus vehicle. *Nociceptive responses to formalin that were significantly greater after SR144528 + THCV or rimonabant + THCV than after THCV alone (P < 0.05).

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