The role of cannabinoid receptors in intestinal motility, defaecation and diarrhoea in rats

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Abstract

We have studied the effects of the cannabinoid receptor agonists (R)-(+)[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN 55,212-2, 0.3–5 mg/kg, i.p.) and (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) (CP 55,940, 0.03–1 mg/kg, i.p.), the cannabinoid CB1 receptor antagonist (N-piperidin-1-yl)-5-(4-chlorophenyl)-1-2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A, 0.3–5 mg/kg, i.p.) and the cannabinoid CB2 receptor antagonist 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 (SR144528, 1 mg/kg, i.p.) on intestinal motility, defaecation and castor-oil (1 ml/100 g rat, orally)-induced diarrhoea in the rat. SR141716A, but not SR144528, increased defaecation and upper gastrointestinal transit, while WIN 55,212-2 and CP 55,940 decreased upper gastrointestinal transit but not defaecation. WIN 55,212-3 (5 mg/kg), the less active enantiomer of WIN 55,212-2, was without effect. A per se non-effective dose of SR141716A (0.3 mg/kg), but not of SR144528 (1 mg/kg) or the opioid receptor antagonist, naloxone (2 mg/kg i.p.), counteracted the inhibitory effect of both WIN 55,212-2 (1 mg/kg) and CP 55,940 (0.1 mg/kg) on gastrointestinal motility. WIN 55,212-2 did not modify castor-oil-induced diarrhoea, while CP 55,940 produced a transient delay in castor-oil-induced diarrhoea at the highest dose tested (1 mg/kg), an effect counteracted by SR141715A (5 mg/kg). These results suggest that (i) intestinal motility and defaecation could be tonically inhibited by the endogenous cannabinoid system, (ii) exogenous activation of cannabinoid CB1 receptors produces a reduction in intestinal motility in the upper gastrointestinal tract but not in defaecation, (iii) endogenous or exogenous activation of cannabinoid CB2 receptors does not affect defaecation or intestinal motility and (iv) the cannabinoid receptor agonist, CP 55,940, possesses a weak and transient antidiarrhoeal effect while the cannabinoid receptor agonist, WIN 55,212-2, does not possess antidiarrhoeal activity.

Introduction

Cannabinoid receptors are the molecular targets of hashish and marijuana, the drugs of abuse obtained from Cannabis sativa L. (Cannabinaceae). Two classes of cannabinoid receptors, named CB1 and CB2, have been identified (Pertwee, 1997). The cannabinoid CB1 receptor occurs in the brain (Matsuda et al., 1990), where it is responsible for psychoactive effects of cannabis and in certain peripheral tissues Gérard et al., 1991, Kaminski et al., 1992, Schlicker et al., 1996, whereas the cannabinoid CB2 receptor is present outside the nervous system (Munro et al., 1993), mostly in cells of the immune system, presumably mediating cannabinoid-induced immunosuppression and possibly also antinflammatory effects (Pertwee, 1997). The guinea-pig myenteric plexus-longitudinal muscle preparation contains cannabinoid binding sites that closely resemble cannabinoid CB1 receptors in the guinea-pig brain (Ross et al., 1998).

Results from functional experiments have led to the conclusion that activation of cannabinoid CB1 receptors can mediate the inhibition of electrically evoked contractions in the guinea-pig Pertwee et al., 1996, Izzo et al., 1998b and human ileum (Croci et al., 1998), while the selective cannabinoid CB1 receptor antagonist, (N-piperidin-1-yl)-5-(4-chlorophenyl)-1-2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A), potentiates excitatory transmission in the guinea-pig ileum Pertwee et al., 1996, Izzo et al., 1998b but not in the human ileum (Croci et al., 1998).

Cannabinoids also modulate intestinal motility in vivo. Activation of cannabinoid CB1 receptors inhibits while blockade of cannabinoid CB1 receptors increases defaecation (Izzo et al., 1999) and upper gastrointestinal transit in mice Calignano et al., 1997, Colombo et al., 1998, Izzo et al., 1999. From the above, it appears that the role of cannabinoid receptors in intestinal motility in vivo has been studied exclusively in the mouse. The present study was performed to investigate the role of cannabinoid receptors in intestinal motility and defaecation in the rat. In addition, since marijuana is a traditional remedy to treat diarrhoea (Grinspoon and Bakalar, 1993), the potential antidiarrhoeal activity of cannabinoids was also evaluated. For these purposes, the cannabinoid receptor agonists, (R)-(+)[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN 55,212-2) and (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) (CP 55,940) Compton et al., 1992, Pertwee, 1997, the cannabinoid CB1 receptor antagonist, SR141716A (Rinaldi-Carmona et al., 1995), and the cannabinoid CB2 receptor antagonist, 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 (SR144528) (Rinaldi-Carmona et al., 1998), were used. Antidiarrhoeal activity was studied using the castor-oil test. This test has been used extensively in several laboratories as a basic pharmacological test to screen and evaluate antidiarrhoeal drugs.

Section snippets

Animals

Male Sprague–Dawley rats (Fondazione “Mario Negri” Sud, Imbaro, Chieti), weighing 170–200 g were used after 1 week of adaptation to the housing conditions (23±2°C; 60% humidity). The animals were deprived of food 3 h before the experiments on faecal excretion and 12 h before the experiments on intestinal motility and diarrhoea. All animal experiments complied with the Italian D.L. no. 116 of 27 January 1992 and associated guidelines in the European Communities Council Directive of 24 November

Upper gastrointestinal transit

Administration of the cannabinoid CB1 receptor antagonist, SR141716A (0.3–5 mg/kg), dose-dependently enhanced upper gastrointestinal transit (Fig. 1). This effect was significant (P<0.05) for the 1–5 mg/kg doses. In contrast, WIN 55,212-2 and CP 55,940 significantly inhibited intestinal motility from 1 mg/kg and 0.1 mg/kg onward respectively and this effect was dose-related (Fig. 1). WIN 55,212-3, the less active isomer of WIN 55,212-2, did not significantly affect intestinal motility (%

Discussion

Recent findings indicate that cannabinoid CB1 receptors can modulate intestinal motility, based on the findings that cannabinoid receptor agonists are able to depress intestinal motility both in vitro and in vivo and that these effects are counteracted by SR141716A, a specific cannabinoid CB1 receptor antagonist Pertwee et al., 1996, Colombo et al., 1998, Izzo et al., 1998b, Izzo et al., 1999. In the mouse, activation of cannabinoid CB1 receptors decreases, while blockade of cannabinoid CB1

Acknowledgements

This work was supported by CNR, MURST and the Enrico and Enrica Sovena Foundation. The authors thank Mr. Domenico Addeo for his help.

References (28)

  • D.R. Compton et al.

    Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from Δ9-tetrahydrocannabinol

    J. Pharmacol. Exp. Ther.

    (1992)
  • T. Croci et al.

    Stimulation of faecal excretion in rats by α-adrenergic antagonist

    J. Pharm. Pharmacol.

    (1992)
  • T. Croci et al.

    In vitro functional evidence of neuronal cannabinoid CB1 receptors in human ileum

    Br. J. Pharmacol.

    (1998)
  • W.A. Devane et al.

    Isolation and structure of a brain constituent that binds to the cannabinoid receptor

    Science

    (1992)
  • Cited by (0)

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