Targeting the Endocannabinoid System for Gastrointestinal Diseases: Future Therapeutic Strategies

Rudolf Schicho; Martin Storr

Disclosures

Expert Rev Clin Pharmacol. 2010;3(2):193-207. 

In This Article

Pharmacological Targets of the ECS in GI Disease

Emesis

A prominent feature of eating disorders and cancer chemotherapy that can be influenced by cannabinoids is vomiting (emesis). Animal models have demonstrated that cannabinoid ligands reduce vomiting.[85,86,97] The involved receptors, CB1 and TRPV1, are located in the brainstem and have been suggested to play a key role in the regulation of emesis. In addition, CB2 receptors are also present in the brainstem and inhibit vomiting in the ferret when stimulated together with CB1.[98] The maintenance of an endogenous tone by anandamide-stimulated CB1s may be the most important mechanism in the control of emesis during physiological states.[86] High levels of anandamide in the brainstem, therefore, may be useful in pathophysiological conditions, such as nausea. They can be generated by FAAH and EMT blockers that prolong the action of anandamide by inhibiting its degradation or its clearance from the extracellular space.[99] In fact, the FAAH blocker, URB597, was used successfully to suppress lithium-induced nausea in rats[100] and decreased morphine 6-glucoronide-induced emesis in ferrets.[86] Blockade of the EMT with VDM11 prevented emesis in the least shrew.[101]

It has been known for years that Cannabis inhibits vomiting induced by chemotherapy.[97] Cannabinoid compounds are now being introduced into clinical practice for the prevention of emesis in patients receiving chemotherapy, especially when the symptomatic control of emesis with 5-hydroxytryptamine (5-HT3) receptor antagonists, and dexamethasone has failed.[102] The synthetic cannabinoid compound, nabilone, has been approved recently for the treatment of chemotherapy-induced nausea (Cesamet®, Valeant Pharmaceuticals, CA, USA). A systematic review of the literature suggests nabilone as being superior to the placebo, domperidone or prochlorperazine, but not to metoclopramide or chlorpromazine.[103] In a meta-analysis, nabilone and dronabinol demonstrated clear superiority over neuroleptic antiemetics in cancer chemotherapy.[104] However, treating emesis with cannabinoids may not be without concern, since administration of 2-AG – but not of anandamide – induces vomiting in the least shrew,[101] maybe not directly via CB1 but via cyclooxygenase-dependent downstream metabolites.[105] The main reason why the use of cannabinoids during chemotherapy remains unsatisfactory is because cannabinoids cause severe psychotropic side effects, such as depression and hallucinations.[102] Nevertheless, patients show a clear preference to cannabinoid medication and a 'high' sensation could be considered as a beneficial side effect.[106] To be comprehensive, it needs to be mentioned that cases of paroxysmal vomiting with compulsive hot bathing have been reported in patients with chronic Cannabis use.[107–109] The etiology of this symptom, however, is not yet known.

Gastroesophageal Reflux Disease & Gastric Ulcer

Gastroesophageal reflux is caused by transient lower esophageal sphincter relaxation (TLESR) triggered by postprandial gastric distension. Derangement of the sphincter mechanism may also contribute to gastroesophageal reflux disease. CB1 agonists have shown to inhibit TLESR via brainstem mechanisms in dogs[110] and ferrets.[111] In a recent study in humans, Δ9-THC significantly inhibited the increase in meal-induced TLESR and reduced basal lower esophageal sphincter pressure, suggesting the involvement of CBs in TLESR.[112] Since CB1 agonists also inhibit gastric acid secretion,[15,95] they could represent powerful drugs in the treatment of gastroesophageal reflux disease. In several experimental models of gastric ulcer disease, CB1 activation has proved effective in the protection of the gastric mucosa.[113–115]

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a common disorder in the Western world and affects 10–20% of adults.[116] It belongs to the group of so-called functional bowel disorders, which are characterized by the absence of organic abnormalities of the GI tract. Typical symptoms of IBS include abdominal discomfort, pain, bloating and altered bowel habits.[117] The syndrome has been defined recently in the Rome III criteria: recurrent abdominal pain or discomfort for at least 3 days per month over 3 months associated with either an improvement with defecation or a change in stool frequency or stool form.[118] Despite the various symptoms that constitute IBS, three clinical forms can be differentiated: diarrhea-predominant IBS (D-IBS), constipation-predominant IBS (C-IBS) and mixed-form IBS.[117] The pathophysiology of IBS is complex and incorporates biological as well as psychosocial factors (Figure 2).[118] Albeit the absence of organic failure, it is believed that altered gut motility, visceral hypersensitivity and deranged gut–brain signaling underlies the etiology of IBS. Disturbances of motility and visceral hypersensitivity would be suitable for a treatment with cannabinoids because of the important role the ECS plays herein. Beneficial effects of cannabinoids should be mediated via CB1 located on enteric nerves, extrinsic sensory fibers and colon epithelium, while CB2 could play a role in inflammatory conditions acting on cells involved in the immune response. Since IBS consists of a multitude of symptoms, different ligands of CBs, also administered in combination, could fight individual symptoms and, thus, lead to an improvement.

Figure 2.

Effects of the endocannabinoid system (ECS) in irritable bowel syndrome. The ECS is involved in the regulation of many factors during IBS. Arrows indicate each of these factors and show the components of the ECS that are involved. Each of these components may represent targets for a potential treatment. AEA: Anandamide; CB: Cannabinoid receptor; EMT: Endocannabinoid membrane transporter; FAAH: Fatty acid amide hydrolase.

IBS & Motility Gut motility and central pain processing has been investigated in IBS patients (reviewed in[119]). In D-IBS, for instance, colonic transit time is accelerated and high-amplitude-propagated contractions are increased,[120–122] whereas in C-IBS, transit is slower.[123,124] A consistent finding in IBS patients is that they display exaggerated phasic colonic contractions after a meal,[121,122,125] although this alone cannot explain the entire syndrome. Two reasons would make it worthwhile to investigate cannabinoids in IBS. First, cannabinoids have an important role in the motor control of the GI tract and, second, altered gut motility is a potential factor in IBS etiology. Agonists of CB1s have all been demonstrated to inhibit gut motility in vitro.[18,126] According to a new study, it also seems that the peristaltic reflex is under tonic control of CB1.[127] Therefore, agonists of CB1 would be helpful in managing diarrhea, while antagonists of CB1 could be used in the treatment of constipation and dyspepsia that frequently overlaps with IBS.[128] CB2 receptors may regulate gut motility during inflammatory conditions.[30] Testing CB2 in IBS would be of interest owing to the changed bowel motility we observe in these patients.

IBS & Secretion Any disturbances in fluid secretion and water absorbance will lead to diarrhea. CB1 stimulation has been demonstrated to inhibit electrical stimulation-induced ileal secretion in rats.[129] Castor oil- and cholera toxin-induced diarrhea in rodents were also inhibited by CB1 agonists.[44,130] The role of endocannabinoids in secretion has not been yet evaluated in IBS, although it would be worthwhile, considering the antidiarrheal abilities of CB1 agonists and the obvious fact that Cannabis has been used for centuries in traditional medicine treating diarrhea. The antidiarrheal abilities of CB1 agonists are probably a combination of their depressing effects on excitatory transmitter release and over-reactivity in the myenteric plexus[34] (resulting in a slowdown of motility) and on transmitter release from extrinsic primary afferents that normally act on cholinergic secretory pathways in submucosal ganglia[16] (resulting in reduced secretion).

IBS & Visceral Hypersensitivity Another common symptom of IBS is abdominal pain, and it is thought that both peripheral and central mechanisms contribute to its development.[131–133] In particular, sensitization of visceral afferent fibers by acute or chronic inflammation could be involved in the generation of abdominal pain.[132–135] Studies in animal models have shown that cannabinoids produce analgesic effects and play an important role in visceral sensation.[136–138] Thus, activation of CBs by CB1 and CB2 agonists reduced the visceromotor response in rodents to graded colorectal distension.[138] Hyperalgesia induced by TNBS colitis lowered the amounts of CB agonists needed to reduce sensitivity to colorectal distension, suggesting that, in hypersensitive states, patients might be more susceptible to cannabinoid treatment.[137,138] Where exactly CB1and CB2 agonists act to regulate visceral pain is still not clear. A peripheral site of action is possible, since bradykinin-induced activity in mesenteric afferents were reduced by a CB2 agonist in vivo[139] and a peripherally restricted CB1 agonist was able to reduce pain during colorectal distension.[140] It is not known whether these agonists would act the same way in humans but, in a randomized placebo-controlled study, the CB1 and CB2 ligand dronabinol relaxed the colon, reduced postprandial colonic motility and increased sensation, while gas sensation thresholds were unchanged.[141] To reduce visceral sensation, CBs could interact with other analgesic receptors, such as k-opioid receptors (KORs), which colocalize with CBs in myenteric neuronal cell cultures[13] and are able to reduce sensation to colorectal distension in IBS patients upon activation.[142] In this context, it is interesting that Salivinorin A, the active ingredient of the plant Salvia divinorum, exerts both KOR- and CB1-/CB2-sensitive effects on motility and secretion in the mouse colon in vitro,[143] and reduces ileitis-induced hypermotility via KOR and CB1in vivo.[144] TRPV1, which can be activated by anandamide, also has been implicated in visceral hypersensitivity to colorectal distension of rodents,[145] and is believed to act comparably in humans. An increased density of TRPV1 immunoreactive nerve fibers has been demonstrated in biopsies of patients with IBS.[146] Blockade of TRPV1 in visceral hyperalgesia may be superior to that of CB1 because application of the CB1 antagonist rimonabant causes hypoalgesia during repeated colorectal distension, something that is not observed during treatment with TRPV1 antagonists.[147] Altogether, it would be worth targeting CB1, CB2 and TRPV1 simultaneously to see a synergistic or additive effect on pain sensation. FAAH blockers, such as N-arachidonoyl-serotonin that also act as TRPV1 antagonists[148] may become useful drugs for the treatment of hypersensitivity associated with IBS. In an animal model of visceral nocieception, pharmacological inhibition and genetic deletion of FAAH demonstrated analgesic effects and reduced the severity of gastric irritations caused by diclofenac.[149]

IBS & Gut Microbiota An increasing number of studies support the concept that bacterial overgrowth plays a role in the pathophysiology of IBS.[150] Certain probiotics have been observed to reduce visceral hypersensitivity in rats and mice[151,152] and to alleviate symptoms in IBS patients.[153]Lactobacillus acidophilus increased CB2 mRNA expression in cultured epithelial cells in vitro and in colonic epithelial cells in vivo after chronic treatment, while the CB2 antagonist, AM630, prevented the L. acidophilus-induced reduction of rectal sensitivity.[154] It is however not clear how a change in epithelial expression of CB2 could influence visceral sensitivity. No data are available yet on CB1, FAAH or the roles they could play in the interaction with microbiota. Further studies are needed to explore how microbiota influence the ECS and regulate CB expression.

IBS & Genetics A single-nucleotide polymorphism (C385A) has been discovered recently in the FAAH gene,[155] which enhances sensitivity to proteolytic degradation.[156] In this study, the FAAH polymorphism was associated with accelerated colonic transit in patients with D-IBS but not with C-IBS and mixed form-IBS. The functional alterations caused by the FAAH polymorphism, however, are not yet fully characterized. It should be noted that IBD patients do not display such genetic associations.[157]

Inflammatory Bowel Disease

There are approximately 2.2 million people in Europe and 1.4 million in North America who suffer from inflammatory bowel attacks.[158] These attacks are often signs of an idiopathic, chronic and relapsing inflammation of the GI tract, termed IBD, and manifest mainly in two clinical forms, ulcerative colitis and Crohn's disease. A growing number of studies demonstrated that the ECS may play a significant role in GI inflammation and IBD. Levels of anandamide are elevated in rectum biopsies from patients with ulcerative colitis.[52] In addition, CB expression is increased in response to GI inflammation in animal models. In croton oil-induced intestinal inflammation and in DSS colitis of mice, CB1 is increased in myenteric ganglia of the colon,[28,41,42] while mRNA for CB2 is increased in full-thickness samples of the colon during TNBS-induced colitis.[45] CB2 upregulation was also noticed in infiltrated cells of the colon mucosa during DSS colitis[28] and in human colonic mucosa during IBD.[12] Anecdotal reports exist that patients suffering from IBD experience relief when smoking marijuana,[5] indicating that stimulation of CB receptors is protective in intestinal inflammation. This has been confirmed by studies in mice that demonstrated an improvement of colitis parameters after CB1 or CB2 stimulation,[28,41,45] although some protective effects have been described for the CB1 antagonist, rimonabant, in indomethacin-induced ileitis in rats.[159] Conversely, experimentally induced colitis is worse in CB1- or CB2-knockout mice or mice treated with CB1 or CB2 antagonists.[41,45] How CB receptors contribute to the improvement of colitis is not completely understood but an effect on the colon epithelium is quite conceivable. CB1s have been observed to promote wound healing of colon epithelial cells[12] and activation of CB2 inhibited TNF-α-induced IL-8 release in HT-29 cells.[160] CB1 and CB2 agonists may also reduce hypermotility and diarrhea during IBD, as previously shown in animal models.[42,161] Blockade of FAAH activity and anandamide reuptake in order to increase endogenous anandamide levels are also protective.[52,157] Owing to the changes in FAAH expression during experimental colitis[45,162] and the presence of a FAAH gene polymorphism (C385A) in D-IBS, FAAH polymorphism was also investigated in patients with Crohn's disease. However, no significant difference was detected between Crohn's patients and healthy people.[157] In summary, there is strong indication that CBs and endocannabinoids play a key role in the protection against GI inflammation.[163] Pharmacological intervention of the ECS for the treatment of IBD would, therefore, be extremely useful (Box 1).

Colon Cancer

Cannabinoids have recently received much interest as a potential therapy in colorectal cancer, which is one of the leading causes of death after lung cancer in the Western hemisphere.[164] The interest is based on the cannabinoids' ability to suppress proliferation and to induce apoptosis in tumor cells.[48,165,166] Studies in colorectal cancer cell lines indicate that the antiproliferative and apoptotic effects are mediated via CB1 and, depending on the investigated cell line, maybe via CB2.[48,167] Anandamide inhibits migration of colon carcinoma cells via CB1[168] and induces a nonapoptotic, non-necrotic cell death that involves COX-2 expression.[169] Since colorectal tumor cells express high levels of COX-2,[170] which promotes tumorigenesis,[171] anandamide would be very useful in the treatment of tumor cells that have become resistant to apoptosis.[169] CB1-induced apoptosis involves several pathways and mechanisms, such as inhibition of RAS–MAPK and PI3K–AKT pathways,[167] downregulation of the antiapoptotic factor survivin[172] and activation of ceramide.[173] In particular, ceramide seems to be an important downstream mediator of CB during apoptosis of human colon cancer cells. Both CB1 and CB2 activation have been demonstrated to induce apoptosis in DLD-1 and HT29 cells via TNF-α-sensitive ceramide synthesis.[174] It should be also noted that CB1 could play a role in the antiproliferative effects of estrogens because 17β-estradiol induces CB1 gene expression in a variety of human colon cancer cells.[175] Adaptive changes of ECS components were also demonstrated during carcinogenesis. Endocannabinoids, such as anandamide and 2-AG, were increased several-fold in adenomas and colorectal cancer compared with normal mucosa,[48] while CB1 but not CB2 was downregulated in colon carcinoma, indicating that absence of CB1 promotes colon carcinogenesis.[172] The effects of cannabinoid drugs on colon carcinoma have been mostly studied in tumor models using azoxymethane-treated and adenomatous polyposis coli (APC) mice. azoxymethane is a carcinogen that induces early neoplastic lesions, so-called aberrant crypt foci, which occurs with a simultaneous rise in 2-AG levels.[54] The FAAH inhibitor, N-arachidonoylserotonin, reduces aberrant crypt foci formation, indicating that high levels of endocannabinoids have an impact on neoplastic lesion development.[54] APC mice are used as a model to study cancer progression. They have a germ-line mutation in the APC (tumor-suppressor) gene that causes spontaneous development of intestinal polyps. Using this model, Wang et al. could show that the antitumor effects of CB1 seen in vitro also apply to in vivo models of colon cancer.[172] Knockout of the CB1 gene in APC mice or treatment with the CB1 antagonist, AM251, increased colonic cancer burden compared with their littermates.[172] In this cancer model, the authors also found a high rate of DNA methylation of the CNR1 promotor, indicating epigenetic silencing of the CB1 gene.

In summary, cannabinoid drugs could be protective in colorectal cancer, either through activation of CB1 or through enhancement of endocannabinoid levels by FAAH inhibition. Although the potential use of cannabinoids as antitumor drugs is still in a preclinical phase, in the meantime, they may serve as valuable supportive drugs for cancer patients to alleviate pain and nausea during chemotherapy.

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