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Review Cannabinoids and the Gastrointestinal Tract

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Review Cannabinoids and the Gastrointestinal Tract Gut 2001;48:859–867 859 Review Gut: first published as 10.1136/gut.48.6.859 on 1 June 2001. Downloaded from Cannabinoids and the gastrointestinal tract 2 Summary receptors. CB1 receptors are found mainly on neurones in The enteric nervous system of several species, including the brain, spinal cord, and peripheral nervous system, one the mouse, rat, guinea pig and humans, contains cannabi- of their functions being to modulate neurotransmitter noid CB1 receptors that depress gastrointestinal motility, release. The physiological roles of CB2 receptors, which are mainly by inhibiting ongoing contractile transmitter expressed mainly by immune cells, are proving more diY- release. Signs of this depressant eVect are, in the whole cult to establish. Endogenous ligands for cannabinoid organism, delayed gastric emptying and inhibition of the receptors have been identified, the most important being transit of non-absorbable markers through the small intes- anandamide (arachidonylethanolamide) and 2-arachidonyl tine and, in isolated strips of ileal tissue, inhibition of glycerol (2-AG). There is evidence that anandamide, and evoked acetylcholine release, peristalsis, and cholinergic possibly also 2-AG, are removed from the extracellular and non-adrenergic non-cholinergic (NANC) contractions space by a carrier mediated uptake process that is present of longitudinal or circular smooth muscle. These are con- in neurones and astrocytes.34 Once within the cell, tractions evoked electrically or by agents that are thought anandamide is hydrolysed to arachidonic acid and to stimulate contractile transmitter release either in tissue ethanolamine by the enzyme fatty acid amide hydrolase taken from morphine pretreated animals (naloxone) or in (FAAH).3 This microsomal enzyme, which is found both in unpretreated tissue (ã-aminobutyric acid and neurones and in some non-neuronal tissues, can also cata- 5-hydroxytryptamine). The inhibitory eVects of cannabi- lyse the hydrolysis of 2-AG. The “endocannabinoids”, noid receptor agonists on gastric emptying and intestinal anandamide and 2-AG, and their receptors constitute the transit are mediated to some extent by CB1 receptors in the “endocannabinoid system”. brain as well as by enteric CB receptors. Gastric acid 56 1 As detailed elsewhere, a wide range of ligands for CB1 secretion is also inhibited in response to CB receptor acti- 1 and CB2 receptors have now been developed. Most notable vation, although the detailed underlying mechanism has among the CB1 selective ligands are the agonists (R)-(+)- yet to be elucidated. Cannabinoid receptor agonists delay arachidonyl-1'-hydroxy-2'propylamide (methanandam- gastric emptying in humans as well as in rodents and prob- ide), arachidonyl-2'-chloroethylamide, and arachidonyl- ably also inhibit human gastric acid secretion. Cannabi- cyclopropylamide, and the antagonists/inverse agonists noid pretreatment induces tolerance to the inhibitory SR141716A and LY320135. Of the CB1 selective agonists, eVects of cannabinoid receptor agonists on gastrointestinal methanandamide is less susceptible than anandamide to http://gut.bmj.com/ motility. Findings that the CB1 selective antagonist/inverse hydrolysis by FAAH. Important CB2 selective ligands agonist SR141716A produces in vivo and in vitro signs of include the agonists L759633, L759656, JWH-133, and increased motility of rodent small intestine probably reflect HU-308, and the antagonist/inverse agonist SR144528. the presence in the enteric nervous system of a population Inhibitors of endocannabinoid uptake and metabolism are 56 of CB1 receptors that are precoupled to their eVector also now available. Among these are the anandamide mechanisms. SR141716A has been reported not to behave uptake inhibitor N-(4-hydroxyphenyl) arachidonylamide in this manner in the myenteric plexus-longitudinal muscle (AM404), and the potent FAAH inhibitors palmityl- on September 25, 2021 by guest. Protected copyright. preparation (MPLM) of human ileum unless this has first sulphonyl fluoride (AM374) and stearylsulphonyl fluoride been rendered cannabinoid tolerant. Nor has it been found (AM381). Many of the experiments described in this to induce “withdrawal” contractions in cannabinoid toler- review have been performed with cannabinoid receptor ant guinea pig ileal MPLM. Further research is required to agonists that have similar aYnities for CB1 and CB2 recep- investigate the role both of endogenous cannabinoid tors. Of these, the most commonly used have been receptor agonists and of non-CB1 cannabinoid receptors in WIN55212, which exhibits marginal CB2 selectivity, the the gastrointestinal tract. The extent to which the eVects on “classical” cannabinoid Ä9-THC, and the “non-classical” gastrointestinal function of cannabinoid receptor agonists cannabinoid CP55940.56 These agonists contain chiral or antagonists/inverse agonists can be exploited therapeu- centres and show marked stereoselectivity in both binding tically has yet to be investigated as has the extent to which and functional assays. For classical and non-classical these drugs can provoke unwanted eVects in the gastro- cannabinoids, those with the same absolute stereochemis- intestinal tract when used for other therapeutic purposes. 9 try as (−)-Ä -THC at 6a and 10a (6aR, 10aR)havethe greater activity (the (−)-enantiomers). However, for The endocannabinoid system WIN55212, the R-(+) enantiomer is the more active. The plant Cannabis sativa is the source of a set of more than There is now good evidence for the presence of CB1 and 60 oxygen containing aromatic hydrocarbon compounds CB receptors in the gastrointestinal tract. This article called cannabinoids, of which Ä9-tetrahydrocannabinol 2 9 summarises this evidence and also considers what is (Ä -THC) is the main psychotropic constituent. Of the currently known about the precise location of these recep- other plant cannabinoids, those which have been most tors and the eVects they mediate. investigated are Ä8-THC which has similar pharmacologi- cal properties to Ä9-THC, cannabinol, which has much weaker psychotropic properties than Ä9-THC, and can- 1 Abbreviations used in this paper: MPLM, myenteric plexus- nabidiol, which lacks psychotropic activity. The eVects of 9 9 9-THC are mediated primarily by cannabinoid receptors, longitudinal muscle preparation; Ä -THC, Ä -tetrahydrocannabinol; Ä 2-AG, 2-arachidonyl glycerol; FAAH, fatty acid amide hydrolase; at least two types of which are present in mammalian AM404, N-(4-hydroxyphenyl) arachidonylamide; L-NAME, G tissues. These are CB1 and CB2 receptors and both are N -nitro-L-arginine methyl ester; AER, ascending enteric reflex; NANC, members of the superfamily of G protein coupled non-adrenergic non-cholinergic; PMSF, phenylmethylsulphonyl fluoride. www.gutjnl.com 860 Pertwee Cannabinoids inhibit electrically evoked of human or guinea pig ileum is concentration depend- contractions of isolated small intestine ent and the relationship between log concentration and The ability of cannabinoids to inhibit electrically evoked response is sigmoid in nature.91012131718 contractions of isolated preparations of small intestine xThe rank order of potencies of cannabinoids for inhibi- Gut: first published as 10.1136/gut.48.6.859 on 1 June 2001. Downloaded from mounted in organ baths and the underlying mechanisms tion of electrically evoked contractions of guinea pig have been the subject of many investigations over the past MPLM or whole ileum correlates well with that of their 30 years. These have involved experiments, mainly with psychotropic potencies and of their aYnities for specific 10 12–14 19 guinea pig tissue, in which contractions have been CB1 binding sites in brain tissue (see also produced by electrical stimulation of prejunctional neu- Pertwee2). rones rather than by direct stimulation of intestinal smooth x Using a quantitative autoradiographic binding tech- muscle. nique, Lynn and Herkenham20 demonstrated that Among the first of these experiments were those Peyer’s patches from rat intestinal tract contain high described by Gill and colleagues.78 They investigated the aYnity specific binding sites for [3H]CP55940 and that response of the guinea pig isolated ileum to Ä9-THC or to the aYnities of a selected range of cannabinoids for these various subfractions of petrol soluble and petrol insoluble binding sites correspond reasonably closely to their fractions of tincture of cannabis BPC, then still a licensed aYnities for [3H]CP55940 binding sites of rat brain. medicine in the UK. The petrol insoluble fraction was They also found [3H]CP55940 to be more potently dis- found to contain material with atropine-like properties that placed from its Peyer’s patch binding sites by (−)-Ä9- opposed ileal contractions which had been evoked either by THC or CP55940 than by the (+)-enantiomers of these electrical stimulation or by acetylcholine. It also contained cannabinoids or by cannabidiol, each of which has rela- two substances with muscarinic properties that induced tively low cannabinoid receptor aYnity. Although Lynn contractions of resting ileum. Two subfractions of the pet- and Herkenham20 were able to visualise [3H]CP55940 rol soluble fraction also proved to have pharmacological binding sites in Peyer’s patches located in rat jejunum, activity. These were an ether eluate (fraction III) and one ileum, and rectum by autoradiography, they did not component of an ether/petroleum spirit eluate that observe such binding sites elsewhere in these regions of contained Ä9-THC (fraction IIc). The eVects
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