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Cannabinoids and gastrointestinal motility: Animal and human studies

Article  in  European review for medical and pharmacological sciences · September 2008

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Barbara Romano

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Introduction

The marijuana plant Cannabis has been usedfor the treatment of a number of diseases includ-ing those affecting gastrointestinal motility1-4. ∆9-tetrahydrocannabinol (∆9-THC), the main activeingredient of Cannabis, activates two Gi/o-cou-pled membrane receptors, named CB1 and CB2

receptors. Cannabinoid CB1 receptors are locatedprimarily on central and peripheral neurons, in-cluding those innervating the gut, whereas CB2

receptors are mainly expressed by inflammatory/immune cells5.

Endogenous ligands that activate cannabinoidreceptors [(i.e. the endocannabinoids, anan-damide and 2-arachydonylglycerol (2-AG)] havebeen identified in mammalian tissues, and theirlevels increase after exposure of animals to nox-ious stimuli as well as in intestinal biopsies ofpatients with colon cancer, diverticulitis and celi-ac disease6-10. Endocannabinoids are biosynthe-sized ‘on demand’ from membrane phospho-lipids and released from cells immediately aftertheir production. Following receptor activationand induction of a biological response, endo-cannabinoids are inactivated through a two-stepprocess: (i) first through a reuptake process facil-itated by a putative membrane transporter where-by endocannabinoids are transported into cells,and (ii) subsequent enzymatic degradation by thefatty acid amide hydrolase (FAAH)5,10. There ispharmacological and biochemical evidence thatproteins involved in endocannabinoid biosynthe-sis and inactivation are present in the gut. Boththe anandamide-biosynthesizing N-acyl-phos-phatidyl-ethanolamine-selective phospholipase D(NAPE-PLD) and the metabolizing enzymeFAAH have been identified in the rodent gut, al-though their precise localization is still elusive.NAPE mRNA has been found in the rodent stom-

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Abstract. – The plant Cannabis has beenknown for centuries to be beneficial in a vari-ety of gastrointestinal diseases, includingemesis, diarrhea, inflammatory bowel diseaseand intestinal pain. ∆∆9-tetrahydrocannabinol,the main psychotropic component of Cannabis,acts via at least two types of cannabinoid re-ceptors, named CB1 and CB2 receptors. CB1

receptors are located primarily on central andperipheral neurons (including the enteric ner-vous system) where they modulate neuro-transmitter release, whereas CB2 receptorsare concerned with immune function, inflam-mation and pain. The discovery of endoge-nous ligands [i.e. anandamide and 2-arachi-donoyl glycerol (2-AG)] for these receptors in-dicates the presence of a functional endoge-nous cannabinoid system in the gastrointesti-nal tract.

Anatomical and functional evidence sug-gests the presence of CB1 receptors in themyenteric plexus, which are associated withcholinergic neurons in a variety of species, in-cluding in humans. Activation of prejunctionalCB1 receptors reduces excitatory enteric trans-mission (mainly cholinergic transmission) indifferent regions of the gastrointestinal tract.Consistently, in vivo studies have shown thatcannabinoids reduce gastrointestinal transit inrodents through activation of CB1, but not CB2,receptors. However, in pathophysiologicalstates, both CB1 and CB2 receptors could re-duce the increase of intestinal motility inducedby inflammatory stimuli. Cannabinoids also re-duce gastrointestinal motility in randomizedclinical trials. Overall, modulation of the gutendogenous cannabinoid system may providea useful therapeutic target for disorders ofgastrointestinal motility.

Key Words:

Cannabinoid receptors, Anandamide, Intestinalmotility, Myenteric plexus, Gastric emptying, Fatty acidamide hydrolase, Irritable bowel syndrome, Inflamma-tory bowel disease.

European Review for Medical and Pharmacological Sciences 2008; 12(Suppl 1): 81-93

Corresponding Author: Angelo A Izzo, MD; e-mail: aaizzo@unina.it

Cannabinoids and gastrointestinal motility:animal and human studies

G. AVIELLO, B. ROMANO, A.A. IZZO

Department of Experimental Pharmacology and Endocannabinoid Research Group, University ofNaples Federico II, Naples (Italy)

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ach11 and in enterocytes and lamina propria cellswithin the small intestine12. FAAH has been de-tected in different regions of the rodent gastroin-testinal tract, and its inhibition results in reduc-tion of gastrointestinal motility13,14, protectionagainst experimental colitis7,15 and antitumoraleffects16. There is at present no direct evidencefor the existence of a membrane transporter forendocannabinoid reuptake in the gut; however,functional studies suggest that this process mightbe involved in some experimental pathophysio-logical states such as inflammation7 and diar-rhea17.

Although endocannabinoids have been impli-cated in the control of a number of importantphysiological and pathophysiological functionsin the digestive tract, including emesis18, gastro-protection19,20, intestinal ion transport21, inflam-

mation7,9, visceral sensation22 cell proliferationand cancer16,23,24, this review will deal with therole of the endogenous cannabinoid system in thecontrol of gastrointestinal motility.

Cannabinoid Receptors in the DigestiveTract: Focus on the Myenteric Pplexus

There is evidence for the presence of both CB1

and CB2 receptors in the gut. While CB2 recep-tors have been mostly identified in inflammato-ry/immune cells25,26, CB1 receptors have beenfound on epithelial cells, smooth muscle cells,inflammatory/immune cells and in neurons,which include extrinsic afferent sensory neurons,vagal efferents and the neurons of the enteric ner-vous system (Figure 1)3.

G. Aviello, B. Romano, A.A. Izzo

Figure 1. Polarized enteric motor pathways involved in control of intestinal motor activity and localization of CB1 receptors.Peristalsis occurs in response to radial distension of the intestinal wall. Distention activates enteric reflexes, which include anascending excitatory reflex leading to contraction at the oral end via the release of excitatory transmitters such as acetylcholine(ACh) and tachykinins (Tk), and a descending inhibitory reflex which causes relaxation of the smooth muscle at the aboral endvia the release of inhibitory transmitters such as NO and ATP. The coordinated oral contraction and anal relaxation enables theintestinal bolus to be transported in the anal direction. Neurons in this pathway include intrinsic sensory neurons, which re-spond to mechanical or chemical stimuli, motor neurons, which may cause either contraction (excitatory motor neurons) or re-laxation (inhibitory motor neurons) and interneurons (orally and anally projecting), which connect sensory neurons to motorneurons. CB1 receptor (indicated with the marijuana leaf) immunoreactivity has been identified on intrinsic sensory neurons,ascending interneurons and final excitatory motor neurons (cholinergic and possibly tachykinergic neurons) projecting to thelongitudinal and circular muscles. The presence of CB1 receptors on inhibitory motor neurons (possibly purinergic neurons),mediating relaxant effects via the fast (apamin-sensitive) inhibitory junction potential has been hypothesized on the basis offunctional studies. No colocalization between CB1 receptor immunoreactivity and NO synthase has been observed. Pharmaco-logical evidence suggests that the main site of action of cannabinoid drugs is the CB1 receptor located on the final excitatorycholinergic motor neurons whose activation leads to a reduction of acetylcholine release.

The enteric nervous system is formed by twomajor plexuses, called the submucosal plexus,which is primarily involved in the control of intesti-nal ion transport, and the myenteric plexus, whichplays an important role in the control of intestinalmotility. The myenteric plexus lies between the lon-gitudinal and circular layers of muscle and extendsover the entire length of the gut27-29. The neuronsthat make up the enteric nervous system can beclassified as intrinsic primary afferent neurons, in-terneurons, and motor neurons. Intrinsic primary af-ferent neurons, which form the sensory limb of allintrinsic motor reflexes, are all cholinergic and mayor may not contain substance P. CB1 receptor im-munoreactivity colocalizes with cholinergic nervescontaining calbindin, a marker for intrinsic primaryafferent neurons in the guinea pig ileum30. Interneu-rons are interposed between the primary afferentneurons and the motor neurons. Interneurons in-volved in motor reflexes are directed orally or anal-ly and are designated as ascending or descending,respectively. Ascending excitatory cholinergic neu-rons of the guinea pig ileum are calretinin im-munoreactive and express CB1 receptors30. The mo-tor neurons can be classified as excitatory neurons,which contract smooth muscles through the releaseof acetylcholine and tachykinins, and inhibitorymotor neurons, which relax smooth musclesthrough the release of nitric oxide (NO), adenosinetriphosphate (ATP) or vasoactive intestinal polypep-tide (VIP). CB1 immunoreactivity completely colo-calizes with the marker of cholinergic neuronscholine acetyltransferase in the guinea pig30, rat30,porcine31 and human32,33 intestine. Colocalization ofCB1 receptors with substance P immunoreactiveneurons (or unidentified noncholinergic excitatorymotor neurons) has been also reported30,31,34. Thesedata suggest that CB1 receptors are associated withcholinergic and noncholinergic excitatory motorneurons. Finally, the presence of CB1 receptors oninhibitory motor neurons (possibly purinergic neu-rons), mediating depressant effects on the fast(apamin-sensitive) inhibitory junction potential hasbeen hypothesized on the basis of functional studiesonly. On the other hand, several studies have report-ed that in the myenteric plexus there is no overlapbetween NO synthase and CB1 receptor immunore-activity31,35.

Animal Studies on Gastrointestinal Motility

Cannabinoids have been shown to reduce gas-tric, small intestinal and colonic motility both in

isolated segments and in vivo studies in rodents.This effect is largely mediated by CB1 receptoractivation, although CB2 receptors may be in-volved in some pathophysiological states.

Animal Studies in vitro

It is generally accepted that cannabinoid ago-nists act on prejunctional CB1 receptors to reducesmooth muscle contractility, ascending neuralcontractions and peristalsis in different regions ofthe gastrointestinal tract. The mechanisms bywhich CB1 activation reduces contractility aremainly related to reduction of acetylcholine re-lease from enteric nerves, although other mecha-nisms, such as inhibition of nonadrenergic non-cholinergic (NANC) excitatory transmission havebeen proposed2,8,36.

Excitatory TransmissionTransmission from cholinergic and NANC ex-

citatory neurons has been evaluated in various in-testinal segments and in a number of animalspecies. Results suggest that activation of CB1 re-ceptors reduce cholinergic and possibly NANCexcitatory transmission. The action resembles theputative effects of µ-opioid receptor and α2-adrenoceptor agonists in intestinal tissues.

Cholinergic TransmissionCholinergic excitatory neurons supply both the

longitudinal and the circular muscle of the stom-ach, small intestine and large intestine. The re-ceptor for acetylcholine on the muscle has beenshown to be the M3 subtype muscarinicreceptor37. Cannabinoid receptor agonists, in-cluding the plant-derived ∆9-THC and the en-dogenous cannabinoid agonist anandamide havebeen shown to reduce electrically-induced con-tractions in different regions of the gastrointesti-nal tract, including the rodent stomach38,39, smallintestine40,41 and colon42. Both the longitudinaland the circular muscle are generally responsiveto the inhibitory action of cannabinoid receptoragonists. Detailed studies in the guinea pig ileum(Table I) have shown that cannabinoid-inducedinhibition of contractility was competitively andreversibly antagonized by CB1 receptor antago-nists, without any effect on the inhibitory re-sponses to morphine (µ-opioid receptor agonist)or clonidine (α2-adrenoceptor agonist)40,41. It islikely that cannabinoids reduce (via CB1 receptoractivation) electrically-induced contractions by

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Cannabinoids and gastrointestinal motility: animal and human studies

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decreasing acetylcholine release from entericnerves; indeed, cannabinoid agonists (i) did notmodify the contractions produced by exogenousacetylcholine which evokes contractions by a di-rect action on muscarinic receptors located on in-testinal smooth muscle)40,41, but (ii) reduced elec-trically-evoked acetylcholine release from myen-teric nerves43.

In a single study involving intracellularrecordings from neurons of the guinea pig myen-teric plexus-longitudinal muscle preparation,cannabinoid receptor agonists were found to in-hibit fast and slow excitatory synaptic transmis-sion. In a subset of the neurons tested, this effectwas reversed by the CB1 receptor antagonist ri-monabant44.

Nonadrenergic Noncholinergic (NANC)Excitatory Transmission

The release of enteric excitatory substancesother than acetylcholine has been assumed be-cause residual responses to nerve stimulation aredetected after the actions of cholinergic nerveshave been blocked by atropine28. In the circularmuscle of guinea pig ileum, in the presence of at-ropine and guanethidine, high frequency electri-cal field stimulation of enteric nerves produces acontractile response which is mediated by the re-lease of tachykinins from postganglionic neu-rons. In this preparation anandamide and the syn-thetic cannabinoid agonist WIN55,212-2 reducedthe NANC excitatory response produced by elec-trical stimulation in a CB1 receptor-sensitivemanner40. As both cannabinoid receptor agonistsdid not inhibit the contractions produced by ex-ogenous substance P, it was assumed that

cannabinoids inhibit the NANC contraction byacting prejunctionally rather than through a di-rect action on intestinal smooth muscle. Consis-tent with these results, immunohistochemicalstudies reported localization of CB1 receptors tosubstance P-immunoreactive neurons30,31,34.

Inhibitory NeurotransmissionIn the gastrointestinal tract, a major part of the

inhibitory autonomic innervation appears to beprovided by NANC nerves, which have two ormore primary transmitters, including NO andATP (or a related purine). The nonnitrergic com-ponent of the inhibitory transmission is blockedby apamin, an inhibitor of the small-conductanceCa2+-activated K+ channels. NANC inhibitorynerves are present throughout the gastrointestinaltract in all species and their blockade results indisruption of peristalsis28. Although there is noimmunohistochemical evidence for the presenceof CB1 receptors on NANC inhibitory nerves,functional studies indicate that cannabinoids mayaffect enteric inhibitory transmission in rodents.Focal electrical stimulation of intrinsic neuronsof isolated strips of the mouse proximal colon in-duces a transient excitatory junction potential(EJP, abolished by atropine) followed by a fast(transient) inhibitory junction potential (fIJP),which represents the apamin-sensitive compo-nent of the mouse inhibitory transmission, and aslow (sustained) inhibitory junction potential (sI-JP) which represents the NO-dependent compo-nent of the mouse inhibitory transmission.WIN55,212-2 (in a CB1 receptor antagonist-sen-sitive manner) significantly reduced the EJP andfIJP, but not sIJP, suggesting that CB1 receptor

G. Aviello, B. Romano, A.A. Izzo

Table I. Potency (ED50) of cannabinoid receptor agonists in reducing electrically-induced contractions (EFS) in the guinea pigileum, upper gastrointestinal transit (UGT) and colonic motility in the mouse in vivo (intraperitoneal administration).

*The IC50 was 289 nM in the presence of a FAAH inhibitor; **after i.v. administration; ***data refer to the rat (from Di Carloand Izzo, 2003, reference 1).

Guinea pig ileum EFS-induced contractions Mouse UGT Mouse colonic motility

Cannabinoid IC50 (nM) ED50 (mg/kg) ED50 (mg/kg)

Anandamide 8823* 4.24 4.73WIN 55,212-2 5.54 0.262 0.375ACEA Not studied 0.203 0.174 Cannabinol 3913 7.784 11.203D9-THC 214 1.3** Not studiedCP55,940 3.46 0.047*** Not studied

activation reduces the apamin-sensitive compo-nent of the inhibitory transmission in the mousecolon45. However, by using a pharmacologicalapproach (i.e. EFS-induced relaxation of isolatedintestinal tissues), it has been recently shown thatcannabinoids do not modulate NANC inhibitorytransmission in the mouse stomach and colon38,42.

Ascending Excitatory ReflexThe ascending excitatory reflex (AER) is a

neurogenic orally-directed motor response of thecircular musculature which is triggered by gutwall distention. The reflex involves intrinsic sen-sory neurons, interneurons and motor neurons.Transmission between these neurons and to themuscle involves nicotinic and muscarinic acetyl-choline receptors as well as tachykinin recep-tors28. Heinemann et al showed that methanan-damide inhibited the AER contraction elicited byballoon distension46. Since methanandamide alsodepressed hexamethonium-resistant AER (whichdepends on tachykinergic neuroneural transmis-sion), it was suggested that methanandamide in-terrupts both cholinergic and noncholinergicjunctions within ascending enteric neural path-ways46. To establish the site of action of cannabi-noids on specific enteric neural pathways, Yueceet al used a mouse small intestine preparation setup in a partitioned bath in which ascending nervepathways were stimulated electrically to activatesynaptically excitatory motor neurons to the cir-cular muscle. Thus, the action of cannabinoiddrugs on the ascending enteric nerve pathwaywas studied without interfering with the record-ing of the smooth muscle contractions (Figure2)47. It was found that anandamide inhibited as-cending neural contractions evoked by electricalstimulation only when added to the oral com-partment (where contractions were recorded) andnot when added to the aboral compartment,where only neurons but not the neuromuscularsite was in contact with anandamide. These re-sults suggest that the main site of action of anan-damide is the CB1 receptor located on the neuro-muscular unit47.

Peristalsis Peristalsis is a coordinated pattern of motor

behavior which occurs in the gastrointestinaltract and allows the contents to be propelled inthe anal direction. Because peristalsis is con-trolled primarily by the enteric nervous systemand does not depend on inputs from extrinsicneurons, it can be studied in isolated segments of

intestine27,28. In the isolated guinea pig small in-testine, two phases of peristalsis have been de-scribed in response to the slow infusion of liquidwhich radially stretches the intestinal wall: apreparatory phase, in which the intestine gradual-ly distends until a threshold distension and anemptying phase, in which the circular muscle atthe oral end of the intestine contracts, an effectfollowed by a wave of contraction that propa-gates aborally along the intestine. The pathwaysmediating peristalsis involve intrinsic sensoryneurons and interneurons, as well as excitatoryand inhibitory motor neurons. Acetylcholine act-ing through both muscarinic and nicotinic recep-tors and tachykinins are excitatory neurotrans-mitters participating in the peristaltic activity,whereas VIP, NO and an apamin-sensitive in-hibitory transmitter (possibly ATP or a relatedpurine) act as inhibitory mediators28,29.

The cannabinoid agonists WIN55,212-2 andCP55,940 inhibited peristalsis in the guinea pigileum as deduced from (i) the decreased longitu-dinal smooth muscle reflex contraction and theincreased threshold pressure and volume requiredto elicit peristalsis during the preparatory phasesof peristalsis and (ii) the reduction of maximalejection pressure during the emptying phase of

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Cannabinoids and gastrointestinal motility: animal and human studies

Figure 2. Partitioned bath for the separate application ofcannabinoid drugs to enteric nerve pathways and the record-ing of the resulting contraction of the circular muscle. Thepartitioned bath enables drugs to be applied to enteric nervepathways (i.e. in the aboral compartment) without interfer-ing with the recording of the smooth muscle contraction(which occurs in the oral compartment). By using this parti-tioned bath, it has been demonstrated that anandamide re-duced (via CB1 receptor activation) the ascending neuralcontraction evoked by electrical stimulation only whenadded to the oral compartment. Adapted from Yuece et al.2007, reference 47.

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peristalsis48. These effects were antagonized bythe CB1 receptor antagonist rimonabant, which,in absence of any agonist, increased maximalejection pressure during the emptying phase ofperistalsis. In a different work, it was found thatmethanandamide, a metabolically stable ana-logue of the endocannabinoid anandamide, in-creased (via CB1 receptor activation) the peri-staltic pressure threshold, which is suggestive ofinhibitory effect on peristalsis46. The antiperi-staltic effect of methanandamide was reduced bythe NO synthase inhibitor L-NAME and inhibit-ed by apamin which blocks neuromuscular trans-mission from motor neurons mediated by ATP(or a related purine). Moreover, when cholinergictransmission was blocked by atropine or hexam-ethonium (in which case peristalsis is mediatedby the release of endogenous tachykinins), theactivity of methanandamide to depress peristalsiswas preserved. These findings further confirmthat cannabinoids inhibit NANC excitatory trans-mission in the guinea pig ileum.

Mancinelli et al elicited peristaltic activity bydistention of the isolated mouse distal colon49.Intraluminal pressure, longitudinal displacement,ejected fluid volume and changes in the morphol-ogy of the external intestinal wall were recorded.In the pre-drug (control) period, peristaltic activi-ty was characterized by regular, monophasicwaves, and the intraluminal content was pro-pelled in an oro-aboral direction. The cannabi-noid receptor agonist WIN55,212-2 (in a CB1 re-ceptor antagonist-sensitive manner) caused adose-related attenuation of peristaltic activityconsequent to the decrease of circular and longi-tudinal muscle strength. The decrease of contrac-tile activity was followed by a dose-dependentdecrease in the amount of fluid ejected duringperistalsis. The CB1 receptor antagonist rimona-bant, administered alone, enhanced both tonicand phasic motor activities in the colonic longitu-dinal smooth muscle49.

Spontaneous MotilityThe effect of cannabinoid drugs has been re-

cently evaluated on the spontaneous contractile ac-tivity of the longitudinal muscle in the mouse iso-lated ileum which displays spontaneous contrac-tions50. The endocannabinoid anandamide, the se-lective cannabinoid CB1 receptor agonist, ACEA,but not the selective cannabinoid CB2 receptor ag-onist, JWH 133 reduced the spontaneous mechani-cal activity. The inhibitory effect of ACEA, whichconsisted in a decrease of the mean amplitude of

longitudinal spontaneous contractions (withoutchanges in the resting tone), was significantly an-tagonized by the selective cannabinoid CB1 recep-tor antagonist, rimonabant, but not by the selectivecannabinoid CB2 receptor antagonist, AM630.Furthermore, the ACEA-induced reduction ofspontaneous contractions was nearly abolished bytetrodotoxin and atropine. The authors concludedthat activation of neural CB1 receptors may play arole in the control of spontaneous mechanical ac-tivity through inhibition of acetylcholine releasefrom cholinergic nerve50.

Animals Studies in vivo

Animal studies in vivo have shown that endo-cannabinoids (via CB1 receptor activation) con-stitute a physiological “brake” along the gas-trointestinal tract. This concept is based on thefindings of (i) a high amount of endocannabi-noids in intestinal tissues50, (ii) the strategic loca-tion of CB1 receptors on neurons of the myen-teric plexus34,35, (iii) inhibitory actions ofcannabinoid agonists, including the endocannabi-noid anandamide, on gastric and intestinal motil-ity13,51, (iv) prokinetic effects of the CB1 receptorantagonist rimonabant13,35,51, (v) increased gas-trointestinal transit in CB1 receptor-deficientmice47, and (vi) a depressant action on motility ofinhibitors of anandamide inactivation13,35,52.Cannabinoids also reduce motility in the in-flammed gut and this effect may be mediated byboth CB2 receptors and hyper-expressed myen-teric CB1 receptors25.

Gastric MotilityA number of cannabinoid receptor agonists,

including anandamide, 9-THC, WIN55,212-2, CP55,940 and cannabinol reduce gastric motility inmice and rats and this effect is antagonized bythe CB1 receptor antagonist rimonabant, but notby the CB2 receptor antagonist SR14452813,53,54,55.Most notably, intravenous 9-THC inhibited gas-tric motility and decreased intragastric pressurein anesthetized rats. Also, the application of 9-THC directly to the dorsal surface of the medullaevoked very slight changes in gastric motor ac-tivity. Both ganglionic blockade and vagotomy,but not spinal cord transection, abolished the gas-tric motor effects of peripherally administered 9-THC54. Taken together, these data indicate thatthe gastric effects of systemically administered 9-THC depend on an intact vagal circuitry.

G. Aviello, B. Romano, A.A. Izzo

Intestinal MotilityThe ability of cannabinoids to reduce intesti-

nal motility has been known before the discov-ery of cannabinoid receptors. In 1972, Dewey etal first reported the effect of a cannabinoid onthe rate of passage of a charcoal meal along thesmall intestine56. These authors demonstratedthat 9-THC was at least ten times less potent thanmorphine in mice in delaying intestinal motility.These results were confirmed by Chesher et al(1973), who also showed that 8-THC and threedifferent Cannabis extracts dose-dependentlyreduced the passage of a charcoal meal inmice57. 8-THC and 9-THC were shown to beequipotent, while cannabidiol was inactive57. Ina more complete study, Shook and Burks (1989)reported that 9-THC and cannabinol slowedsmall intestinal transit when injected intra-venously in mice and rats. It was noteworthythat when injected intravenously, 9-THC wasfound to be equipotent to morphine in delayingintestinal motility58.

More recently, the ability of cannabinoids toreduce intestinal motility has been related to theirability to activate cannabinoid CB1 receptors.Studies have shown that endogenous, syntheticand plant-derived cannabinoids inhibited intesti-nal transit and colonic propulsion in mice (TableI) and rats35,59-63, an effect counteracted by the se-lective CB1 receptor antagonist rimonabant, butnot by the CB2 receptor antagonist SR144528 orby the opioid receptor antagonist naloxone. No-tably, the inhibitory effect of anandamide was notreduced by the transient receptor potential vanil-loid type-1 (TRPV1) channel antagonist cap-sazepine or by a chronic treatment with capsaicin(a treatment which ablates capsaicin-sensitive af-ferent neurons)60, thus implying that the effect ofanandamide on intestinal transit is independentof TRPV1 activation.

Cannabinoids were significantly more effec-tive when administered intracerebroventricularly(i.c.v.) than when administered intraperitoneal-ly35,63 suggesting a central site of action. Howev-er, central CB1 receptors probably contribute lit-tle to the effect of peripherally administeredcannabinoids as the effect of intraperitoneally in-jected cannabinoid receptor agonists was notmodified by the ganglion blocker hexamethoni-um35,63. The primary role of peripheral (enteric)CB1 receptors was emphasized by the observa-tion that i.c.v. administered rimonabant did notsignificantly reduce the effect of intraperitonealWIN55,212-255.

Carai et al investigated whether tolerance de-velops after repeated administration of thecannabinoid receptor antagonist rimonabant.Mice were treated intraperitoneally twice a dayfor up to 8 consecutive days with rimonabant. Onday 1, rimonabant markedly activated intestinalperistalsis, but complete tolerance to this effectdeveloped within the third day of treatment64.

Motility Under Pathophysiological StatesThe presence of dysmotility in inflammatory

diseases of the small and large intestine is a well-recognized and clinically accepted phenomenon.Changes in the endogenous cannabinoid systemduring inflammation may alter and/or contributeto these motility changes. Depending of the in-flammatory insult, both CB1 and CB2 receptoractivation may reduce hypermotility associatedwith gut inflammation. In the model of ileitis in-duced in mice by the irritant croton oil, intestinalCB1 receptors are hyper-expressed and cannabi-noid agonists are consequently more active in re-ducing transit compared to control mice51).Moreover, using CB1-deficient mice, Sibaev et alshowed that such receptors are involved in earlyprotective mechanisms against electrophysiologi-cal disturbances (i.e. disturbances in the neuro-muscular unit) initiated in the distal colon bydinitrobenzene sulphonic acid administration65.On the other hand, in the lipopolysaccharidemodel of intestinal hypermotility in the rat, theCB1 receptor-mediated control of intestinalmotility was completely replaced by a CB2 re-ceptor-mediated mechanism. Indeed, in these an-imals, hypermotility was normalized by a CB2,but not by a CB1 receptor agonist66.

Lower Esophageal Sphincter RelaxationGastroesophageal reflux disease refers to re-

flux of gastric contents into the esophagus lead-ing to esophagitis, reflux symptoms sufficient toimpair quality of life, or long-term complica-tions. Transient relaxation of the loweresophageal sphincter (LES) is believed to be theprimary mechanism of the disease, although theunderlying cause remains uncertain67. The princi-pal anatomical components of LES relaxation areafferent gastric pathways, an integrative center inthe brainstem, and efferent inhibitory pathwaysto the LES. Cannabinoid receptor agonists inhib-ited (via CB1 receptor activation) LES relaxationin dogs68 and ferrets69, the effect being associat-ed, at least in the dog, with inhibition of gastroe-sophageal reflux68. Central and peripheral vagal

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mechanisms are involved in these functionalchanges. This is in agreement with the observa-tion that CB1 receptor staining is present in cellbodies within the dorsal vagal complex (i.e. thearea postrema, nucleus of the solitary tract andnodose ganglion)68.

Human Studies on Gastrointestinal Motility

In Vitro Studies on Cholinergic Transmission

Immunohistochemical and pharmacologicalevidence suggests that CB1 receptors are func-tionally present in the human ileum and colon;their activation results in inhibition of cholinergictransmission subserving contraction of both thecircular and longitudinal muscle32,70-72. A numberof cannabinoid receptor agonists, including thenonselective cannabinoid agonist WIN55,212-2and the selective CB1 receptor agonist ACEA, in-hibited the contractions evoked by electricalstimulation without affecting the contractions in-duced by endogenous agonists such as carbacholor acetylcholine. Immunohistochemical studieslocalized CB1 receptors to cholinergic neurons inthe intestine (particularly in the circular muscle)based on colabelling with choline acetyltrans-ferase32. By contrast, the CB1 receptor agonistACEA did not significantly modify electricallyevoked relaxation of both circular and longitudi-nal muscle preparations, thus suggesting a negli-gible effect on human colonic inhibitory trans-mission32.

Diverticular disease is often associated withmotor abnormalities of the affected colonic seg-ment73. Guagnini et al compared the in vitro con-tractile response to electrical field stimulation oflongitudinal smooth muscle strips from colonicsegments close to diverticula with that ofanatomically healthy segments from patientswith nonobstructive colon cancer, which servedas controls6. In the healthy colon, the cannabi-noid agonist WIN55,212-2 inhibited electricallyevoked contractions and this effect was competi-tively antagonized by rimonabant; moreover, theCB1 receptor antagonist rimonabant had no in-trinsic effects, being unable to inhibit electricaltwitches6. Unlike the healthy colon strips, thosefrom diverticular disease patients were markedlyless sensitive to the inhibitory action ofWIN55,212-2. In contrast to control tissues, ri-monabant had a marked intrinsic action, as it in-creased twitch contractions in colonic tissues

from diverticular disease patients. These resultssuggest that diverticular strips are tolerant to theinhibitory action of endogenous cannabinoids6. Apossible interpretation of these results is that indiverticular – but not in the healthy – colon thereis a strong tonic inhibitory drive sustained by en-docannabinoids which reduce the release of exci-tatory neurotransmitters through an action at theprejunctional cannabinoid CB1 receptor. Consis-tent with this hypothesis, colonic levels of anan-damide were increased in diverticulitis speci-mens compared to healthy controls6.

Finally, it has recently been demonstrated thatthe endocannabinoids anandamide and 2-AG canexert myogenic inhibitory effects (i.e. inhibitionof acetylcholine-induced contractions) in stripsof human colonic longitudinal and circular mus-cle and that this effect is independent fromcannabinoid receptor activation74.

Clinical StudiesAlthough not all studies yielded similar con-

clusions, data on humans suggest that cannabi-noid agonists reduce gastric emptying. In a ran-domized double blind trial, McCallum et alshowed that oral 9-THC, at a dose used for pre-venting chemotherapy-induced nausea and vom-iting, delayed gastric emptying of a radiolabelledsolid meal in nine male and four female healthysubjects who were experienced cannabis users75.Bateman found that gastric emptying of liquid,measured by real time ultrasound, was unaffectedby intravenous 9-THC (0.5 and 1 mg/kg, a dosewhich produced cannabis-like psychomotor andpsychological effects in humans) in seven fastedcannabis-naïve male volunteers76. Apart from thedifferent doses and techniques to measure motili-ty in the two studies, as well as the choice of hu-man volunteers (Cannabis users vs Cannabisnaïve subjects), it should be noted that there aredifferences in the patterns and the motor mecha-nisms involved in the gastric emptying of solidand liquid foods. Gastric emptying of liquid foodis driven mainly by the tone of the gastric fundus.

Recently, Esfandyari et al have fond that 9-THC administration was associated with a signif-icant delay in gastric emptying of a standard sol-id and liquid meal, and there is a suggestion of agender effect influencing the response to thecannabinoid agonist, as indicated by the border-line gender interaction effect (gastric emptyingreduced in females but not in males)77.

Cannabinoids also modulate colonic motility;specifically, 9-THC administration was associated

G. Aviello, B. Romano, A.A. Izzo

with relaxation of the colon and inhibition of theincrease in tone after the meal78. Increasedcolonic compliance was predominantly due to asignificant effect in female subjects. It was hy-pothesized that a cannabinoid receptor agonistmight be effective in reducing postprandial stim-ulation of colonic propulsion, as occurs in somepatients with diarrhea and urgency associatedwith irritable bowel syndrome or dysautonomia.

Genetic Variation in IBS PatientsIrritable bowel syndrome (IBS) is a highly

prevalent functional gastrointestinal disorder(FGID) affecting up to 3-15% of the generalpopulation in Western countries. It is character-ized by unexplained abdominal discomfort andbowel habit alterations: constipation (C-IBS),diarrhea (D-IBS), or mixed IBS79. In a study of482 patients with a range of functional gas-trointestinal disorders and 252 healthy volun-teers, there was a significant association ofFAAH genotype with FGID phenotype and withspecific individual phenotypes (specificallywith D-IBS and mixed IBS and with accelerat-ed colonic transit in D-IBS). The association ofa genetic variation in metabolism of endo-cannabinoids with symptom phenotype in D-IBS and mixed IBS and with faster colonictransit in D-IBS supports the hypothesis thatcannabinoid mechanisms may play a role in thecontrol of colonic motility80.

Non-cannabinoid Receptor-MediatedEffects

Endocannabinoids may also exert pharmaco-logical actions through activation of the TRPV1channel, of orphan G protein-coupled receptors(such as GPR55) or members of the nuclear re-ceptor family (i.e. the peroxisome proliferator-activated receptor subtype α)81. The most studiedamong these potential targets is TRPV1, which ismainly expressed by primary afferent neurons82.Activation of TRPV1 channels by anandamideresulted in ileitis in rats83 and stimulation ofacetylcholine release from guinea pig myentericnerves84. In addition, there is evidence that TR-PV1 activation by anandamide increases ethylenediamine-induced GABA release from the guineapig myenteric plexus85. However, Bartho et al86

could find no evidence for anandamide activationof capsaicin-sensitive receptors in the isolatedhuman sigmoid colon.

Finally, there is also in vitro evidence that en-docannabinoids may act through non-cannabi-noid receptor, non-TRPV1 mechanisms. Mang etal showed that anandamide inhibited electricallyevoked acetylcholine release in the guinea pigileum and that this effect was not counteractedby cannabinoid or TRPV1 antagonists84. Also, 2-AG contracted the longitudinal smooth musclefrom the guinea pig distal colon in a tetrodotox-in-sensitive manner87. In human tissues, anan-damide and 2-AG inhibited myogenic contrac-tions independent of cannabinoid receptor activa-tion74.

Conclusions

An increasing number of articles has shownthat cannabinoids may reduce intestinal motilityin vivo through activation of CB1 receptors un-der physiological states and under pathophysio-logical states involving hyperexpression of CB1

and/or CB2 receptors. Conversely, blockade ofCB1 receptors resulted in increased motility,which is consistent with the occurrence of diar-rhea in patients which receive the antiobesitydrug rimonabant (CB1 receptor antagonist)88.The major role of cannabinoid receptors seemsto be that of a “braking” mechanism, which op-erates when intestinal functions are over-stimu-lated by excitatory neurotransmitters. Cannabi-noid drugs may restore motility when this ispathologically perturbed. Thus, CB1 receptoragonists or antagonists could represent noveldrugs either to decrease gut motility (e.g.cannabinoid agonists to decrease gut motilityduring diarrhea, inflammation or in IBS pa-tients) or to increase motility (cannabinoid an-tagonists as prokinetic agents).

The main problem with nonselective cannabi-noid receptor agonists is the activation of brainCB1 receptors, resulting in sedation, cognitivedysfunction and psychotropic effects. The un-wanted side effects may be minimized by severalapproaches, such as the development of selectiveCB1 agonists that do not cross the blood-brainbarrier, selective targeting of CB2 receptors sinceCB2 receptors are largely absent from the brain,or the use of inhibitors of endocannabinoid inac-tivation (i.e. FAAH inhibitors and inhibitors ofendocannabinoid reuptake) which increase in-testinal levels of anandamide to act on local CB1

receptors, without central effects.

89

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90

Finally, Cannabis-derived non-psychotropiccannabinoids can avoid cannabinoid-associatedcentral effects. The best studied among thesecompounds is cannabidiol, an antioxidant com-pound which selectively inhibit intestinalmotility in the inflamed – but not in the normal– gut89.

–––––––––––––––––––––––Acknowledgements

Some of the authors’ results discussed in the presentreview article have been partly supported by PRIN,Enrico and Enrica Sovena Foundation and Pirelli R.E.

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