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Involvement of CB1 Receptors and Fatty Acid Amide Hydrolase

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Involvement of CB1 Receptors and Fatty Acid Amide Hydrolase Neurogastroenterol Motil (2008) 20, 919–927 doi: 10.1111/j.1365-2982.2008.01114.x Effect of cannabidiol on sepsis-induced motility disturbances in mice: involvement of CB1 receptors and fatty acid amide hydrolase D. DE FILIPPIS,* T. IUVONE,* A. D’AMICO,* G. ESPOSITO, L. STEARDO, A. G. HERMAN,à P. A. PELCKMANS,§ B. Y. DE WINTER§ & J. G. DE MAN§ *Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy Department of Human Physiology and Pharmacology, University of Rome ‘‘La Sapienza’’, Rome, Italy àLaboratory of Pharmacology, Department of Pharmacology, University of Antwerp, Antwerp, Belgium §Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, Faculty of Medicine, University of Antwerp, Antwerp, Belgium Abstract Sepsis is an inflammatory condition that is in septic mice. Sepsis was associated with a selective associated with reduced propulsive gastrointestinal upregulation of intestinal CB1 receptors without motility (ileus). A therapeutic option to treat sepsis is affecting CB2 receptor expression and with increased to promote intestinal propulsion preventing bacterial FAAH expression. The increase in FAAH expres- stasis, overgrowth and translocation. Recent evidence sion was completely reversed by cannabidiol but suggests that anti-oxidants improve sepsis-induced not affected by AM251. Our results show that sep- ileus. Cannabidiol, a non-psychotropic component of sis leads to an imbalance of the endocannabinoid Cannabis sativa, exerts strong anti-oxidant and anti- system in the mouse intestine. Despite its proven inflammatory effects without binding to cannabinoid anti-oxidant and anti-inflammatory properties, canna- CB1 or CB2 receptors. Cannabidiol also regulates the bidiol may be of limited use for the treatment of activity of fatty acid amide hydrolase (FAAH) which sepsis-induced ileus. is the main enzyme involved in endocannabinoid Keywords cannabidiol, endocannabinoid system, breakdown and which modulates gastrointestinal fatty acid amide hydrolase, septic ileus. motility. Because of the therapeutic potential of cannabidiol in several pathologies, we investigated its effect on sepsis-induced ileus and on cannabinoid INTRODUCTION receptor and FAAH expression in the mouse intes- Marijuana from Cannabis sativa L. and its derivatives tine. Sepsis was induced by treating mice with lipo- have been used in medicine for many centuries. The polysaccharides for 18 h. Sepsis led to a decrease in interest in the therapeutic effects of cannabinoids was gastric emptying and intestinal transit. Cannabidiol renewed by the discovery of cannabinoid CB and CB further reduced gastrointestinal motility in septic 1 2 receptors and their endogenous ligands anandamide mice but did not affect gastrointestinal motility in and 2-arachidonoylglycerol respectively. However, the control mice. A low concentration of the CB antag- 1 well-known psychotropic effects of cannabis have onist AM251 did not affect gastrointestinal motility always raised clinical and ethical questions and a valid in control mice but reversed the effect of cannabidiol therapeutic alternative may be represented by the use of non-psychotropic cannabinoids, such as cannabidiol. Cannabidiol, a bioactive constituent of marijuana, Address for correspondence Joris G. De Man, Laboratory of Experimental Medicine and exerts a wide range of effects including antiepileptic, Pediatrics, Division of Gastroenterology, Faculty of Medicine, anxyolitic, antinauseous, neuroprotective and anti- University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, tumoural activities1–9 without having significant activ- Belgium. 5,10–13 ity on CB1 and CB2 receptors. Because of its Tel: +32 3820 2636; fax: +32 3820 2567; beneficial effect in several pathologies, cannabidiol e-mail: [email protected] Received: 30 October 2007 is regarded as a promising therapeutic compound Accepted for publication: 11 February 2008 (recently reviewed in Refs 3,14). Ó 2008 The Authors Journal compilation Ó 2008 Blackwell Publishing Ltd 919 D. De Filippis et al. Neurogastroenterology and Motility The pharmacological actions of cannabidiol can be 1mgkg)1), AM251 (1 mg kg)1) plus cannabidiol attributed to its anti-oxidative properties5,15 and its (10 mg kg)1) or the cannabidiol vehicle (10% ethanol, interaction with the endocannabinoid system.11,16 10% Tween-80 and 80% saline). Thirty minutes later, Cannabidiol enhances the level of anandamide by the mice were divided into a control and lipopolysac- reducing its degradation and inhibiting its uptake.11 charides (LPS) group receiving, respectively, an i.p. The exact pathways involved in this effect still have to injection of vehicle or LPS (Escherichia coli 055:B5; be elucidated but may include the enzyme fatty acid 20 mg kg)1). Six hours after injection of vehicle or amide hydrolase (FAAH). Fatty acid amide hydrolase LPS, mice received a second i.p. injection of the drug metabolizes endogenous fatty acids, including the under study (cannabidiol 10 mg kg)1, AM251 endocannabinoids anandamide and 2-arachidonoyl- 1mgkg)1, the combination or the vehicle). All drugs glycerol.17 Through its inhibitory effect on the hydro- were injected in a volume ratio of 10 lLg)1 body- lysis of FAAH,18,19 cannabidiol has the potency to weight. Eighteen hours after LPS or vehicle injection, modulate the endocannabinoid system. mice were gavaged with 25 green glass beads (0.4– The endocannabinoid system is upregulated during 0.5 mm in diameter) in 0.5 mL water.34 The mice inflammation of the gastrointestinal tract.20–23 An were then transferred to a wired bottom cage and important inflammatory condition affecting the after 120 min, mice were anaesthetized with diethyl gastrointestinal tract is sepsis, which is associated ether and killed by exsanguination. with inhibition of propulsive intestinal motility (ileus) and mucosal barrier dysfunction. Ileus promotes stasis, Measurement of gastric emptying and overgrowth and translocation of bacteria leading to geometrical centre secondary infections and eventually multiple organ failure.24 The pathogenesis of sepsis is incompletely The abdomen was opened and the stomach was understood and the therapeutic options for the treat- rapidly clamped above the lower oesophageal sphinc- ment of sepsis are scarce. The gastrointestinal tract is a ter and beneath the pylorus to prevent further therapeutic target to treat sepsis because promotion of passage of the beads. The complete gastrointestinal propulsive gastrointestinal motility prevents intestinal tract was gently resected. The small intestine was bacterial stasis and reduces bacterial overgrowth and divided into five segments of equal length and the translocation. We previously reported that sepsis colon was divided into two segments of equal length. increases inducible nitric oxide synthase (iNOS)-posi- Subsequently, the stomach (Segment 1), the five tive residential macrophages in the gastrointestinal intestinal segments (Segments 2–6), the caecum tract and this was prevented after anti-oxidant treat- (Segment 7) and the two colonic segments (Segments ment.25 We recently also showed a beneficial effect of 8 and 9) were cut open and the number of glass beads the anti-oxidant melatonin on sepsis-induced motility in each segment was counted under a stereomicro- disturbances in mice.26 This suggests that reduction of scope. The faeces of each mouse, collected during oxidative stress may be a novel adjunct treatment for 120 min after injection of the glass beads, was also sepsis. Because cannabidiol possesses important anti- examined for the presence of beads and considered as oxidant and anti-inflammatory properties5,15,27–29 and ÔSegment 10Õ. because the endocannabinoid system is activated dur- Gastric emptying (GE) was calculated from the ing sepsis,30–33 the aim of the present study was to equation: investigate the effect of cannabidiol on the sepsis- number of beads in the stomach induced motility disturbances in mice. GE ¼ 1 À  100: total number of beads METHODS The geometric centre (GC), which expresses the relative distribution of the glass beads throughout the Experimental procedure gastrointestinal tract was calculated34 from the equ- All procedures received approval from the Medical ation: Ethical Committee of the University of Antwerp. Male Swiss OF1 mice (30–40 g) were fasted from 9.00 GC ¼Rð%beads per segment  segment numberÞ=100: AM by removing food pellets but with free access to tap water. At 4.00 PM, the mice were weighed and received the first i.p. injection of cannabidiol After counting the glass beads, small intestinal )1 (10 mg kg ), AM251 (a selective CB1 antagonist; tissues were collected for Western blot analysis. Ó 2008 The Authors 920 Journal compilation Ó 2008 Blackwell Publishing Ltd Volume 20, Number 8, August 2008 Cannabidiol and intestinal motility 5 min and centrifuged at 10 000 g for 10 min. Protein Organ bath experiments concentration was determined and equivalent Muscle strips of the mouse jejunum were prepared as amounts (50 lg) of each sample were separated under described previously.35 Briefly, a jejunal segment of reducing conditions in 12% SDS-polyacrylamide mini- the small intestine was gently flushed with Krebs– gel. The proteins were transferred onto nitrocellulose Ringer solution (118.3 mmol L)1 NaCl, 4.7 mmol L)1 membrane according to the manufacturerÕs instruc- )1 )1 KCl, 1.2 mmol L MgSO4, 1.2 mmol L KH2PO4, tions (Bio-Rad Laboratories). The membranes were )1 )1 2.5 mmol L CaCl2, 25 mmol L NaCHO3, 0.026 blocked
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