Max Planck researchers and collaborators from the University in Munich identify the body's own cannabinoid receptor as a protective system against colon inflammation
The development of chronic inflammatory diseases of the gastrointestinal tract such as Crohn's disease and Colitis ulcerosa has not been understood yet, but medication to treat and alleviate these diseases are in high demand. In the current issue of The Journal of Clinical Investigation (15 April 2004) a researcher team from the Max Planck Institute of Psychiatry and from the Ludwig-Maximilans-University Munich were able to show that mutant mice lacking the cannabinoid receptor are much more prone to experimentally induced colon inflammation as compared to wild-type control mice. Moreover, colon muscle activities become uncontrolled after inflammation in these mutant mice. The treatment with cannabinoids was able to alleviate inflammation in wild-type animals. Thus, these results suggest that the endogenous cannabinoid system represents a promising therapeutic target for the treatment of chronic inflammatory diseases of the gastrointestinal tract.
An important defense mechanism of the body after insults is the induction of an inflammation. However, if this response is too strong a destruction of the tissue may occur. Therefore, a balance between pro- and anti-inflammatory responses is very important for the body. Chronic inflammatory diseases of the gastrointestinal tract such as Crohn's disease and Colitis ulcerosa constitute a widespread problem in industrialized countries. These diseases are difficult to be treated successfully and the search for novel therapeutic approaches is of high demand.
During centuries, extracts from Cannabis sativa have been used in folk medicine for the treatment of various gastrointestinal diseases. The most active compound of Cannabis sativa is delta-9-tetrahydrocannabinol, also called THC. The human body contains a receptor for THC and THC-like molecules, the cannabinoid receptor type 1 (CB1). Body's fatty acid-like compounds, called endocannabinoids, are also able to activate CB1 receptors. CB1 receptors and endocannabinoids are not only present in the brain but also in the enteric nervous system. Recent investigations conducted by researchers of the group of Beat Lutz at the Max Planck Institute in Munich and of Martin Storr at the Medical Department II of the Ludwig Maximilans University Munich suggest that the endogenous cannabinoid system provides a protective mechanism to prevent excessive inflammatory responses after an insult and thus helps to maintain the balance between pro- and anti-inflammatory reactions.
Inflammatory responses were experimentally induced by infusion of a sulfonic acid-containing substance into the colon of mice. In addition to wild-type control mice, also CB1 knock-out mice (i.e. mice, lacking the cannabinoid rececptor) were used. On day three after infusion, the degree of inflammation was determined by different methods. CB1 knock-out mice showed a higher degree of inflammation as compared to wild-type control mice (Fig. 1).
Based on these observations, the researchers concluded that the endogenous cannabinoid system mediates protection against inflammation and that it might therefore be possible to enhance this protection by stimulation of CB1 receptors. In fact, the application of a substance (HU210), which is very similar to THC, was able to reduce the inflammation very efficiently (Fig. 2).
The reseachers furthermore investigated another mouse mutant, lacking the gene that is required to degrade endocannabinoids. These mutants contain much increased levels of endocannabinoids. Consequently, these mice were more resistant to inflammation. In another set of experiments, it was shown that the endogenous cannabinoid system enhances its activity during inflammation. The neurons in the colon produce more CB1 receptors upon inflammation. "It is as if the cannabinoid system is an on-demand protection system", explains Beat Lutz.
The mechanism of how the endogenous cannabinoid system prevents or alleviates inflammation has not been understood in detail yet. One of the hallmarks of gastrointestinal inflammation is an enhanced spontaneous activity of the cell membrane potentials in the smooth muscles of the colon. The researchers found that this activity was out of control in CB1 knock-out mice (Fig. 3). This was detected already eight hours after the initiation of the inflammatory process, thus, at a time point when no overt signs of inflammation were observable. It appears that the anti-inflammatory action of CB1 receptors is mainly mediated by a suppression of excessive electrical membrane activities in the colon muscles.
The present investigation suggests that the application of cannabinoids has a promising potential in the therapy of chronic colon diseases. Unfortunately, THC and marijuana induces many undesirable side effects on numerous physiological functions. "One solution of this problem may be to develop substances that are able to activate CB1 receptors but do not cross the blood-brain-barrier", proposes Martin Storr, "this would constrain the activity on peripheral tissues such as the colon and the undesirable effects could be avoided". [BL]
Federico Massa, Giovanni Marsicano, Heike Hermann, Astrid Cannich, Krisztina Monory, Benjamin F. Cravatt, Gian-Luca Ferri, Andrei Sibaev, Martin Storr, Beat Lutz The endogenous cannabinoid system protects against colonic inflammation