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

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

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Free PMC article

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

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

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.

Figures

Figure 1
Figure 1
Structures of CBD and CBDA.
Figure 2
Figure 2
Effect of CBDA (0.05, 0.1, 0.5 or 5.0 mg·kg−1) or VEH administered i.p. 45 min prior to toxin administration. The number of emetic episodes in shrews treated with LiCl (A) or cisplatin (B) was measured. Each bar represents the mean ± SEM (n = 6–8). The asterisks indicate a significant difference from the VEH-treated control animals (*P < 0.05; **P < 0.01, one-way anova).
Figure 3
Figure 3
Effect of CBDA (0.01, 0.1, 0.5, 5.0 mg·kg−1) or VEH administered i.p. to rats 45 min prior to LiCl. The number of conditioned gaping responses was measured during the test trial (A).The number of tongue protrusions was measured during the conditioning trial (B). Each bar represents the mean ± SEM (n = 7–12). The cumulative amount of saccharin solution consumed (mL ± SEM) during a one-bottle consumption test was measured at 30, 120 and 360 min after introduction of the bottle to fluid-restricted rats (C). The asterisks indicate a significant difference from the VEH-treated control animals (*P < 0.02; **P < 0.01; one-way anova).
Figure 4
Figure 4
Effect of WAY100635 (0.1 mg·kg−1) or SAL administered i.p. 15 min prior to CBDA (0.1 mg·kg−1 i.p.) or VEH in LiCl-treated rats. The number of conditioned gaping responses was measured during the test trial (A). Each bar represents the mean number of conditioned gaping responses ± SEM (n = 12). The cumulative amount of saccharin solution consumed (mL ± SEM) during a one-bottle consumption test was measured at 30, 120 and 360 min after introduction of the bottle to fluid-restricted rats (B). Individual one-way anovas for each time point indicate that there is no significant difference between any of the four pretreatment groups (P > 0.05). The asterisks indicate a significant difference from the SAL-VEH-treated control animals (***P < 0.001; one-way anova).
Figure 5
Figure 5
Effect of SR141716A (SR; 1 mg·kg−1) or VEH administered i.p. 15 min prior to CBDA (0.1 mg·kg−1 i.p.) or VEH in LiCl-treated rats. The number of conditioned gaping responses was measured during the test trial (A). Each bar represents the mean number of these responses ± SEM (n = 6–12). The cumulative amount of saccharin solution consumed (mL ± SEM) during a one-bottle consumption test was measured at 30, 120 and 360 min after introduction of the bottle to fluid-restricted rats (B). The asterisks indicate a significant difference from the VEH-treated control animals (**P < 0.002; one-way anova).
Figure 6
Figure 6
Effect of WAY100635 (0.1 mg·kg−1) or SAL administered i.p. on the ability of CBDA (0.1 mg·kg−1 i.p.) to suppress the expression of gaping in rats to a context previously paired with LiCl (a model of anticipatory nausea). Each bar represents the mean number of conditioned gaping responses ± SEM (n = 10). The asterisks indicate a significant difference from the SAL-VEH-treated control animals (**P < 0.01; one-way anova).
Figure 7
Figure 7
Effect of CBDA (0.02, 0.1, 0.5 mg·kg−1) or VEH administered i.p. to shrews 45 min prior to the application of motion. The number of emetic episodes (A) and latency of onset to the first emetic episode (B) induced by a 10 min horizontal motion stimulus (frequency: 1 Hz; amplitude: 40 mm) was measured in shrews. Each bar represents the mean ± SEM, n = 5–15. The asterisks indicate a significant difference from the VEH-treated control animals analysed using one-way anova followed by Dunnett's post hoc test (*P < 0.05; **P < 0.01; ***P < 0.001).
Figure 8
Figure 8
Effect of CBDA (0.01, 0.1, 1.0, 10, 100, 1000 nM) on 8-OH-DPAT-induced stimulation of [35S]GTPγS binding to rat brainstem membranes. Symbols represent mean values ± SEM (n = 6 or 7). Mean Emax and EC50 values for 8-OH-DPAT in panels (A)–(F) that were determined in the presence of VEH (DMSO) or CBDA, together with the 95% confidence limits of these values, are listed in Table 1.
Figure 9
Figure 9
Panel (A) Effect of CBDA on specific binding of [3H]CP55940 to mouse whole brain membranes (n = 6). Its mean Ki value with the 95% confidence limits of this value shown in parentheses is 0.9 μM (0.7 and 1.3 μM). Panel (B) Effect of 10 μM CBDA on CP55940-induced stimulation of [35S]GTPγS binding to mouse whole brain membranes. The mean EC50 and Emax values of CP55940 with their 95% confidence limits shown in parentheses are 12.4 nM (4.3 and 35.8 nM; n = 8) and 64.5% (52.5 and 76.5%), respectively, in the presence of VEH (DMSO), and 66.6 nM (27.0 and 164 nM; n = 8) and 63.3% (53.7 and 72.9%), respectively, in the presence of 10 μM CBDA. The mean apparent KB value of CBDA for this antagonism with its 95% confidence limits shown in parentheses is 1.8 μM (0.6 and 5.5 μM). Panel (C) Effect of CBDA on [35S]GTPγS binding to mouse whole brain membranes (n = 16). None of the five mean values shown are significantly different from zero (column statistics analysis; P > 0.05).

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