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. 2001 Jun;48(6):859–867. doi: 10.1136/gut.48.6.859

Cannabinoids and the gastrointestinal tract

R PERTWEE 1
PMCID: PMC1728337  PMID: 11358910

Abstract

The enteric nervous system of several species, including the mouse, rat, guinea pig and humans, contains cannabinoid CB1 receptors that depress gastrointestinal motility, mainly by inhibiting ongoing contractile transmitter release. Signs of this depressant effect are, in the whole organism, delayed gastric emptying and inhibition of the transit of non-absorbable markers through the small intestine and, in isolated strips of ileal tissue, inhibition of evoked acetylcholine release, peristalsis, and cholinergic and non-adrenergic non-cholinergic (NANC) contractions of longitudinal or circular smooth muscle. These are contractions evoked electrically or by agents that are thought to stimulate contractile transmitter release either in tissue taken from morphine pretreated animals (naloxone) or in unpretreated tissue (γ-aminobutyric acid and 5-hydroxytryptamine). The inhibitory effects of cannabinoid receptor agonists on gastric emptying and intestinal transit are mediated to some extent by CB1 receptors in the brain as well as by enteric CB1 receptors. Gastric acid secretion is also inhibited in response to CB1 receptor activation, although the detailed underlying mechanism has yet to be elucidated. Cannabinoid receptor agonists delay gastric emptying in humans as well as in rodents and probably also inhibit human gastric acid secretion. Cannabinoid pretreatment induces tolerance to the inhibitory effects of cannabinoid receptor agonists on gastrointestinal motility. Findings that the CB1 selective antagonist/inverse agonist SR141716A produces in vivo and in vitro signs of increased motility of rodent small intestine probably reflect the presence in the enteric nervous system of a population of CB1 receptors that are precoupled to their effector mechanisms. SR141716A has been reported not to behave in this manner in the myenteric plexus-longitudinal muscle preparation (MPLM) of human ileum unless this has first been rendered cannabinoid tolerant. Nor has it been found to induce "withdrawal" contractions in cannabinoid tolerant guinea pig ileal MPLM. Further research is required to investigate the role both of endogenous cannabinoid receptor agonists and of non-CB1 cannabinoid receptors in the gastrointestinal tract. The extent to which the effects on gastrointestinal function of cannabinoid receptor agonists or antagonists/inverse agonists can be exploited therapeutically has yet to be investigated as has the extent to which these drugs can provoke unwanted effects in the gastrointestinal tract when used for other therapeutic purposes.



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Selected References

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  1. Anderson P. F., Jackson D. M., Chesher G. B. Interaction of delta9-tetrahydrocannabinol and cannabidiol on intestinal motility in mice. J Pharm Pharmacol. 1974 Feb;26(2):136–137. doi: 10.1111/j.2042-7158.1974.tb09240.x. [DOI] [PubMed] [Google Scholar]
  2. Anderson P. F., Jackson D. M., Chesher G. B., Malor R. Tolerance to the effect of delta9-tetrahydrocannabinol in mice on intestinal motility, temperature and locomotor activity. Psychopharmacologia. 1975 Jul 23;43(1):31–36. doi: 10.1007/BF00437611. [DOI] [PubMed] [Google Scholar]
  3. Basilico L., Parolaro D., Colleoni M., Costa B., Giagnoni G. Cross-tolerance and convergent dependence between morphine and cannabimimetic agent WIN 55,212-2 in the guinea-pig ileum myenteric plexus. Eur J Pharmacol. 1999 Jul 9;376(3):265–271. doi: 10.1016/s0014-2999(99)00389-1. [DOI] [PubMed] [Google Scholar]
  4. Bateman D. N. Delta-9-tetrahydrocannabinol and gastric emptying. Br J Clin Pharmacol. 1983 Jun;15(6):749–751. doi: 10.1111/j.1365-2125.1983.tb01561.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Buckley N. E., Hansson S., Harta G., Mezey E. Expression of the CB1 and CB2 receptor messenger RNAs during embryonic development in the rat. Neuroscience. 1998 Feb;82(4):1131–1149. doi: 10.1016/s0306-4522(97)00348-5. [DOI] [PubMed] [Google Scholar]
  6. Chesher G. B., Dahl C. J., Everingham M., Jackson D. M., Marchant-Williams H., Starmer G. A. The effect of cannabinoids on intestinal motility and their antinociceptive effect in mice. Br J Pharmacol. 1973 Dec;49(4):588–594. doi: 10.1111/j.1476-5381.1973.tb08534.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Colombo G., Agabio R., Lobina C., Reali R., Gessa G. L. Cannabinoid modulation of intestinal propulsion in mice. Eur J Pharmacol. 1998 Feb 26;344(1):67–69. doi: 10.1016/s0014-2999(97)01555-0. [DOI] [PubMed] [Google Scholar]
  8. Coruzzi G., Adami M., Coppelli G., Frati P., Soldani G. Inhibitory effect of the cannabinoid receptor agonist WIN 55,212-2 on pentagastrin-induced gastric acid secretion in the anaesthetized rat. Naunyn Schmiedebergs Arch Pharmacol. 1999 Dec;360(6):715–718. doi: 10.1007/s002109900135. [DOI] [PubMed] [Google Scholar]
  9. Costa B., Colleoni M. SR141716A induces in rats a behavioral pattern opposite to that of CB1 receptor agonists. Zhongguo Yao Li Xue Bao. 1999 Dec;20(12):1103–1108. [PubMed] [Google Scholar]
  10. Costa B., Vailati S., Colleoni M. SR 141716A, a cannabinoid receptor antagonist, reverses the behavioural effects of anandamide-treated rats. Behav Pharmacol. 1999 May;10(3):327–331. doi: 10.1097/00008877-199905000-00009. [DOI] [PubMed] [Google Scholar]
  11. Coutts A. A., Brewster N., Ingram T., Razdan R. K., Pertwee R. G. Comparison of novel cannabinoid partial agonists and SR141716A in the guinea-pig small intestine. Br J Pharmacol. 2000 Feb;129(4):645–652. doi: 10.1038/sj.bjp.0703094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Coutts A. A., Pertwee R. G. Evidence that cannabinoid-induced inhibition of electrically evoked contractions of the myenteric plexus--longitudinal muscle preparation of guinea-pig small intestine can be modulated by Ca2+ and cAMP. Can J Physiol Pharmacol. 1998 Mar;76(3):340–346. [PubMed] [Google Scholar]
  13. Coutts A. A., Pertwee R. G. Inhibition by cannabinoid receptor agonists of acetylcholine release from the guinea-pig myenteric plexus. Br J Pharmacol. 1997 Aug;121(8):1557–1566. doi: 10.1038/sj.bjp.0701301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Croci T., Manara L., Aureggi G., Guagnini F., Rinaldi-Carmona M., Maffrand J. P., Le Fur G., Mukenge S., Ferla G. In vitro functional evidence of neuronal cannabinoid CB1 receptors in human ileum. Br J Pharmacol. 1998 Dec;125(7):1393–1395. doi: 10.1038/sj.bjp.0702190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. DAGIRMANJIAN R., BOYD E. S. Some pharmacological effects of two tetrahydrocannabinols. J Pharmacol Exp Ther. 1962 Jan;135:25–33. [PubMed] [Google Scholar]
  16. Desarnaud F., Cadas H., Piomelli D. Anandamide amidohydrolase activity in rat brain microsomes. Identification and partial characterization. J Biol Chem. 1995 Mar 17;270(11):6030–6035. doi: 10.1074/jbc.270.11.6030. [DOI] [PubMed] [Google Scholar]
  17. Dewey W. L., Harris L. S., Kennedy J. S. Some pharmacological and toxicological effects of 1-trans- 8 and 1-trans- 9 -tetrahydrocannabinol in laboratory rodents. Arch Int Pharmacodyn Ther. 1972 Mar;196(1):133–145. [PubMed] [Google Scholar]
  18. Di Marzo V., Melck D., Bisogno T., De Petrocellis L. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 1998 Dec;21(12):521–528. doi: 10.1016/s0166-2236(98)01283-1. [DOI] [PubMed] [Google Scholar]
  19. Drew W. G., Miller L. L., Wikler A. Effect of 9 -THC on the open-field activity of the rat. Psychopharmacologia. 1972;23(3):289–299. doi: 10.1007/BF00404134. [DOI] [PubMed] [Google Scholar]
  20. Frederickson R. C., Hewes C. R., Aiken J. W. Correlation between the in vivo and an in vitro expression of opiate withdrawal precipitated by naloxone: their antagonism by l-(-)-delta9-tetrahydrocannabinol. J Pharmacol Exp Ther. 1976 Nov;199(2):375–384. [PubMed] [Google Scholar]
  21. Gill E. W., Paton W. D., Pertwee R. G. Preliminary experiments on the chemistry and pharmacology of cannabis. Nature. 1970 Oct 10;228(5267):134–136. doi: 10.1038/228134a0. [DOI] [PubMed] [Google Scholar]
  22. Griffin G., Fernando S. R., Ross R. A., McKay N. G., Ashford M. L., Shire D., Huffman J. W., Yu S., Lainton J. A., Pertwee R. G. Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals. Eur J Pharmacol. 1997 Nov 19;339(1):53–61. doi: 10.1016/s0014-2999(97)01336-8. [DOI] [PubMed] [Google Scholar]
  23. Hanus L., Breuer A., Tchilibon S., Shiloah S., Goldenberg D., Horowitz M., Pertwee R. G., Ross R. A., Mechoulam R., Fride E. HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor. Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14228–14233. doi: 10.1073/pnas.96.25.14228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Heinemann A., Shahbazian A., Holzer P. Cannabinoid inhibition of guinea-pig intestinal peristalsis via inhibition of excitatory and activation of inhibitory neural pathways. Neuropharmacology. 1999 Sep;38(9):1289–1297. doi: 10.1016/s0028-3908(99)00056-8. [DOI] [PubMed] [Google Scholar]
  25. Hine B., Friedman E., Torrelio M., Gershon S. Morphine-dependent rats: blockade of precipitated abstinence by tetrahydrocannabinol. Science. 1975 Feb 7;187(4175):443–445. doi: 10.1126/science.1167428. [DOI] [PubMed] [Google Scholar]
  26. Izzo A. A., Mascolo N., Borrelli F., Capasso F. Defaecation, intestinal fluid accumulation and motility in rodents: implications of cannabinoid CB1 receptors. Naunyn Schmiedebergs Arch Pharmacol. 1999 Jan;359(1):65–70. doi: 10.1007/pl00005325. [DOI] [PubMed] [Google Scholar]
  27. Izzo A. A., Mascolo N., Borrelli F., Capasso F. Excitatory transmission to the circular muscle of the guinea-pig ileum: evidence for the involvement of cannabinoid CB1 receptors. Br J Pharmacol. 1998 Aug;124(7):1363–1368. doi: 10.1038/sj.bjp.0701964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Izzo A. A., Mascolo N., Capasso R., Germanò M. P., De Pasquale R., Capasso F. Inhibitory effect of cannabinoid agonists on gastric emptying in the rat. Naunyn Schmiedebergs Arch Pharmacol. 1999 Aug;360(2):221–223. doi: 10.1007/s002109900054. [DOI] [PubMed] [Google Scholar]
  29. Izzo A. A., Mascolo N., Pinto L., Capasso R., Capasso F. The role of cannabinoid receptors in intestinal motility, defaecation and diarrhoea in rats. Eur J Pharmacol. 1999 Nov 12;384(1):37–42. doi: 10.1016/s0014-2999(99)00673-1. [DOI] [PubMed] [Google Scholar]
  30. Izzo A. A., Mascolo N., Tonini M., Capasso F. Modulation of peristalsis by cannabinoid CB(1) ligands in the isolated guinea-pig ileum. Br J Pharmacol. 2000 Mar;129(5):984–990. doi: 10.1038/sj.bjp.0703116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Izzo A. A., Pinto L., Borrelli F., Capasso R., Mascolo N., Capasso F. Central and peripheral cannabinoid modulation of gastrointestinal transit in physiological states or during the diarrhoea induced by croton oil. Br J Pharmacol. 2000 Apr;129(8):1627–1632. doi: 10.1038/sj.bjp.0703265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Jackson D. M., Malor R., Chesher G. B., Starmer G. A., Welburn P. J., Bailey R. The interaction between prostaglandin E1 and delta 9-tetrahydrocannabinol on intestinal motility and on the abdominal constriction response in the mouse. Psychopharmacologia. 1976 May 28;47(2):187–193. doi: 10.1007/BF00735820. [DOI] [PubMed] [Google Scholar]
  33. Katayama K., Ueda N., Kurahashi Y., Suzuki H., Yamamoto S., Kato I. Distribution of anandamide amidohydrolase in rat tissues with special reference to small intestine. Biochim Biophys Acta. 1997 Aug 16;1347(2-3):212–218. doi: 10.1016/s0005-2760(97)00078-7. [DOI] [PubMed] [Google Scholar]
  34. Krowicki Z. K., Moerschbaecher J. M., Winsauer P. J., Digavalli S. V., Hornby P. J. Delta9-tetrahydrocannabinol inhibits gastric motility in the rat through cannabinoid CB1 receptors. Eur J Pharmacol. 1999 Apr 29;371(2-3):187–196. doi: 10.1016/s0014-2999(99)00165-x. [DOI] [PubMed] [Google Scholar]
  35. Lichtman A. H., Wiley J. L., LaVecchia K. L., Neviaser S. T., Arthur D. B., Wilson D. M., Martin B. R. Effects of SR 141716A after acute or chronic cannabinoid administration in dogs. Eur J Pharmacol. 1998 Sep 18;357(2-3):139–148. doi: 10.1016/s0014-2999(98)00558-5. [DOI] [PubMed] [Google Scholar]
  36. Lynn A. B., Herkenham M. Localization of cannabinoid receptors and nonsaturable high-density cannabinoid binding sites in peripheral tissues of the rat: implications for receptor-mediated immune modulation by cannabinoids. J Pharmacol Exp Ther. 1994 Mar;268(3):1612–1623. [PubMed] [Google Scholar]
  37. López-Redondo F., Lees G. M., Pertwee R. G. Effects of cannabinoid receptor ligands on electrophysiological properties of myenteric neurones of the guinea-pig ileum. Br J Pharmacol. 1997 Sep;122(2):330–334. doi: 10.1038/sj.bjp.0701393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Masur J., Märtz R. M., Carlini E. A. Effects of acute and chronic administration of cannabis sativa and (-) delta9-trans-tetrahydrocannabinol on the behavior of rats in an open-field arena. Psychopharmacologia. 1971;19(4):388–397. doi: 10.1007/BF00404383. [DOI] [PubMed] [Google Scholar]
  39. McCallum R. W., Soykan I., Sridhar K. R., Ricci D. A., Lange R. C., Plankey M. W. Delta-9-tetrahydrocannabinol delays the gastric emptying of solid food in humans: a double-blind, randomized study. Aliment Pharmacol Ther. 1999 Jan;13(1):77–80. doi: 10.1046/j.1365-2036.1999.00441.x. [DOI] [PubMed] [Google Scholar]
  40. Mechoulam R., Ben-Shabat S., Hanus L., Ligumsky M., Kaminski N. E., Schatz A. R., Gopher A., Almog S., Martin B. R., Compton D. R. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995 Jun 29;50(1):83–90. doi: 10.1016/0006-2952(95)00109-d. [DOI] [PubMed] [Google Scholar]
  41. Nalin D. R., Levine M. M., Rhead J., Bergquist E., Rennels M., Hughes T., O'Donnel S., Hornick R. B. Cannabis, hypochlorhydria, and cholera. Lancet. 1978 Oct 21;2(8095):859–862. doi: 10.1016/s0140-6736(78)91569-6. [DOI] [PubMed] [Google Scholar]
  42. Nye J. S., Seltzman H. H., Pitt C. G., Snyder S. H. High-affinity cannabinoid binding sites in brain membranes labeled with [3H]-5'-trimethylammonium delta 8-tetrahydrocannabinol. J Pharmacol Exp Ther. 1985 Sep;234(3):784–791. [PubMed] [Google Scholar]
  43. Pertwee R. G., Browne S. E., Ross T. M., Stretton C. D. An investigation of the involvement of GABA in certain pharmacological effects of delta-9-tetrahydrocannabinol. Pharmacol Biochem Behav. 1991 Nov;40(3):581–585. doi: 10.1016/0091-3057(91)90366-a. [DOI] [PubMed] [Google Scholar]
  44. Pertwee R. G. Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development. Expert Opin Investig Drugs. 2000 Jul;9(7):1553–1571. doi: 10.1517/13543784.9.7.1553. [DOI] [PubMed] [Google Scholar]
  45. Pertwee R. G., Fernando S. R., Griffin G., Abadji V., Makriyannis A. Effect of phenylmethylsulphonyl fluoride on the potency of anandamide as an inhibitor of electrically evoked contractions in two isolated tissue preparations. Eur J Pharmacol. 1995 Jan 5;272(1):73–78. doi: 10.1016/0014-2999(94)00618-h. [DOI] [PubMed] [Google Scholar]
  46. Pertwee R. G., Fernando S. R., Nash J. E., Coutts A. A. Further evidence for the presence of cannabinoid CB1 receptors in guinea-pig small intestine. Br J Pharmacol. 1996 Aug;118(8):2199–2205. doi: 10.1111/j.1476-5381.1996.tb15663.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Pertwee R. G. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther. 1997;74(2):129–180. doi: 10.1016/s0163-7258(97)82001-3. [DOI] [PubMed] [Google Scholar]
  48. Pertwee R. G. Pharmacology of cannabinoid receptor ligands. Curr Med Chem. 1999 Aug;6(8):635–664. [PubMed] [Google Scholar]
  49. Pertwee R. G., Stevenson L. A., Elrick D. B., Mechoulam R., Corbett A. D. Inhibitory effects of certain enantiomeric cannabinoids in the mouse vas deferens and the myenteric plexus preparation of guinea-pig small intestine. Br J Pharmacol. 1992 Apr;105(4):980–984. doi: 10.1111/j.1476-5381.1992.tb09088.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Pertwee R. G. The central neuropharmacology of psychotropic cannabinoids. Pharmacol Ther. 1988;36(2-3):189–261. doi: 10.1016/0163-7258(88)90106-4. [DOI] [PubMed] [Google Scholar]
  51. Piomelli D., Beltramo M., Glasnapp S., Lin S. Y., Goutopoulos A., Xie X. Q., Makriyannis A. Structural determinants for recognition and translocation by the anandamide transporter. Proc Natl Acad Sci U S A. 1999 May 11;96(10):5802–5807. doi: 10.1073/pnas.96.10.5802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Rinaldi-Carmona M., Barth F., Héaulme M., Shire D., Calandra B., Congy C., Martinez S., Maruani J., Néliat G., Caput D. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 1994 Aug 22;350(2-3):240–244. doi: 10.1016/0014-5793(94)00773-x. [DOI] [PubMed] [Google Scholar]
  53. Rivas-V J. F., García R. Inhibition of histamine-stimulated gastric acid secretion by delta 9-tetrahydrocannabinol in rat isolated stomach. Eur J Pharmacol. 1980 Jul 25;65(2-3):317–318. doi: 10.1016/0014-2999(80)90410-0. [DOI] [PubMed] [Google Scholar]
  54. Rosell S., Agurell S. Effects of 7-hydroxy-delta-6-tetrahydrocannabinol and some related cannabinoids on the guinea pig isolated ileum. Acta Physiol Scand. 1975 May;94(1):142–144. doi: 10.1111/j.1748-1716.1975.tb05873.x. [DOI] [PubMed] [Google Scholar]
  55. Ross R. A., Brockie H. C., Fernando S. R., Saha B., Razdan R. K., Pertwee R. G. Comparison of cannabinoid binding sites in guinea-pig forebrain and small intestine. Br J Pharmacol. 1998 Nov;125(6):1345–1351. doi: 10.1038/sj.bjp.0702204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Roth S. H. Stereospecific presynaptic inhibitory effect of delta9-tetrahydrocannabinol on cholinergic transmission in the myenteric plexus of the guinea pig. Can J Physiol Pharmacol. 1978 Dec;56(6):968–975. doi: 10.1139/y78-154. [DOI] [PubMed] [Google Scholar]
  57. Shire D., Carillon C., Kaghad M., Calandra B., Rinaldi-Carmona M., Le Fur G., Caput D., Ferrara P. An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing. J Biol Chem. 1995 Feb 24;270(8):3726–3731. doi: 10.1074/jbc.270.8.3726. [DOI] [PubMed] [Google Scholar]
  58. Shook J. E., Burks T. F. Psychoactive cannabinoids reduce gastrointestinal propulsion and motility in rodents. J Pharmacol Exp Ther. 1989 May;249(2):444–449. [PubMed] [Google Scholar]
  59. Sofia R. D., Diamantis W., Harrison J. E., Melton J. Evaluation of antiulcer activity of delta9-tetrahydrocannabinol in the Shay rat test. Pharmacology. 1978;17(3):173–177. doi: 10.1159/000136851. [DOI] [PubMed] [Google Scholar]
  60. Ueda N., Yamamoto S. Anandamide amidohydrolase (fatty acid amide hydrolase). Prostaglandins Other Lipid Mediat. 2000 Apr;61(1-2):19–28. doi: 10.1016/s0090-6980(00)00052-6. [DOI] [PubMed] [Google Scholar]
  61. Ward S. J., Mastriani D., Casiano F., Arnold R. Pravadoline: profile in isolated tissue preparations. J Pharmacol Exp Ther. 1990 Dec;255(3):1230–1239. [PubMed] [Google Scholar]
  62. Zygmunt P. M., Chuang H., Movahed P., Julius D., Högestätt E. D. The anandamide transport inhibitor AM404 activates vanilloid receptors. Eur J Pharmacol. 2000 May 12;396(1):39–42. doi: 10.1016/s0014-2999(00)00207-7. [DOI] [PubMed] [Google Scholar]

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