Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice

Abstract

Background and purpose: Cannabidiol is a Cannabis-derived non-psychotropic compound that exerts a plethora of pharmacological actions, including anti-inflammatory, neuroprotective and antitumour effects, with potential therapeutic interest. However, the actions of cannabidiol in the digestive tract are largely unexplored. In the present study, we investigated the effect of cannabidiol on intestinal motility in normal (control) mice and in mice with intestinal inflammation.

Experimental approach: Motility in vivo was measured by evaluating the distribution of an orally administered fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; contractility in vitro was evaluated by stimulating the isolated ileum, in an organ bath, with ACh.

Key results: In vivo, cannabidiol did not affect motility in control mice, but normalized croton oil-induced hypermotility. The inhibitory effect of cannabidiol was counteracted by the cannabinoid CB1 receptor antagonist rimonabant, but not by the cannabinoid CB2 receptor antagonist SR144528 (N-[-1S-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide), by the opioid receptor antagonist naloxone or by the alpha2-adrenergic antagonist yohimbine. Cannabidiol did not reduce motility in animals treated with the fatty acid amide hydrolase (FAAH) inhibitor N-arachidonoyl-5-hydroxytryptamine, whereas loperamide was still effective. In vitro, cannabidiol inhibited ACh-induced contractions in the isolated ileum from both control and croton oil-treated mice.

Conclusions and implications: Cannabidiol selectively reduces croton oil-induced hypermotility in mice in vivo and this effect involves cannabinoid CB1 receptors and FAAH. In view of its low toxicity in humans, cannabidiol may represent a good candidate to normalize motility in patients with inflammatory bowel disease.

Figure 1

Inhibitory effect of cannabidiol (CBD, 1–10 mg kg⁻¹, i.p.) on intestinal transit in croton oil-treated mice in vivo. Transit was expressed as the geometric centre (GC) of the distribution of a fluorescent marker along the small intestine. GC ranged from 1 (minimal motility) to 10 (maximal motility) (see Methods section). Bars represent the mean±s.e.mean of 8–10 animals for each experimental group. ^#P<0.05 vs control and ^*P<0.05 vs croton oil.

Figure 2

Croton oil-treated mice: effect of i.p.-injected cannabidiol (CBD, 5 mg kg⁻¹) and loperamide (LOP, 0.075 mg kg⁻¹) (alone or in the presence of the cannabinoid CB₁ receptor antagonist rimonabant (0.1 mg kg⁻¹, i.p.)) on intestinal transit in vivo. Transit was expressed as the geometric centre (GC) of the distribution of a fluorescent marker along the small intestine. GC ranged from 1 (minimal motility) to 10 (maximal motility) (see Methods section). Bars represent the mean±s.e.mean of 8–10 animals. ^#P<0.05 vs control, ^*P<0.05 vs croton oil and °P<0.05 vs CBD.

Figure 3

Croton oil-treated mice: effect of i.p.-injected cannabidiol (CBD, 5 mg kg⁻¹) and the fatty acid amide hydrolase inhibitor N-arachidonoyl-5-hydroxytryptamine (AA-5-HT, 7.5 mg kg⁻¹) (alone or in combination) on intestinal transit in vivo. Transit was expressed as the geometric centre (GC) of the distribution of a fluorescent marker along the small intestine. GC ranged from 1 (minimal motility) to 10 (maximal motility) (see Methods section). Bars represent the mean±s.e.mean of 8–10 animals. ^#P<0.05 vs control, ^*P<0.05 and ^**P<0.05 vs croton oil and °P<0.05 vs LOP.

Figure 4

Inhibitory effect of cannabidiol (0.01–100 μM) on the contractions induced by ACh (1 μM) in the isolated mouse ileum of control and croton oil-treated mice. Each point represents mean±s.e.mean of 7–8 experiments.