Jacob Bell
New Member
Ester Fride
College of Judea and Samaria, Departments of Behavioral Sciences and Molecular Biology, Ariel, Israel
Abstract
The 'endocannabinoid (CB) receptor (ECBR) system', consists of specific receptors and several endogenous ligands. The ECBR system is involved in many physiological functions including immunity, inflammation, neurotoxicity and neurotrauma, epilepsy, depression and stress, appetite, food intake and energy homeostasis, cardiovascular regulation, reproduction, and bone remode¬ling. The brain and gastrointestinal system interact bidirectionally in the regulation of digestive processes, food ingestion and energy balance (hence the 'brain-gut axis'). Emotional stress and and the 'reward' center in the brain modulate the brain-gut axis. ECBR presence in brain, gastroin¬testinal as well as adipose (fat) tissue as well as its involvement in stress and emotional processing, provide it with a major role in food intake, digestion and the regulation of adipose tissue mass and adipocyte endocrine function. With cannabinoid receptors and endocannabinoids present from the early embryonic stages and in maternal milk, the ECBR system seems of critical value for new-born milk ingestion.
It is concluded that (i) the ECBR system is a major mediator between the brain and the digestive system, (ii) the role of the ECBR system in adult regulation of food processing is a remnant of its critical role for the initiation of feeding in the newborn, and (iii) the pervasive influence of the ECBR system in alimentary control, make it a highly suitable target for therapeutic developments for conditions such as inflammatory bowel disease, irritable bowel syndrome, gastric ulcers, nau¬sea, obesity, anorexia and failure-to-thrive.
Key words: CB1, CB2, development, feeding, appetite, gastrointestinal tract, adipose tissue
This article can be downloaded, printed and distributed freely for any non-commercial purposes, provided the original work is prop¬erly cited (see copyright info below). Available online at cannabis medicine
Author's address: Ester Fride, fride@yosh.ac.il
Introduction: the "alimentary control system"
Appetite, hunger and satiety are regulated by a number of hormonal signals emanating from the central ner¬vous system (CNS) and gastrointestinal (GI) tract [1, 2]. It is impossible to separate the appetite-hunger¬satiety signals which regulate food intake, from the digestive processes in the GI tract and secretions from adipose (fat) tissue such as the hormone leptin. There-fore in this review, regulation of food intake, appetite and the brain-gut-adipose system will be considered as one system regulating ingestion and digestion, and will be denoted the "alimentary control system".
The rich bidirectional interactions between the brain and the local neuronal network (the enteric nervous
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system - ENS) in the intestinal system (the 'brain-gut axis'), have been extensively studied. Thus, for e - xample, psychological stress has been shown to affect gut activities such as secretion and motility [3]. Con¬versely, using brain imaging techniques such as func¬tional magnetic resonance imaging (fMRI) or positron emission tomography (PET), it has been demonstrated that visceral sensation resulting from stimulation of the oesophagus, stomach or rectum, resulted in activation of higher brain centers including the somatosensory cortex, thalamus and prefrontal cortex [3].
Ingestion and digestion are controlled by a large num¬ber of hormones which originate from the brain, GI tract and adipose tissue and which act in as a signaling network of mutual influence. The major hormones
include leptin (from adipose tissue), cholecystokinin (CCK), peptide tyrosine (PYY) and orexin A and B [2, 4-6].
Emotional stress and reward
Interestingly, the major hormones (such as corticotro-phic releasing hormone (CRH)) and brain structures involved in modulating emotional and stress responses (such as the hypothalamus and the amygdala) are also important modulators of gastrointestinal tract activity such as GI motility and gastric emptying [1]. Conver¬sely, hormones associated with gastrointestinal functi¬oning such as the gastrin-releasing peptide (GRP), and ghrelin, affect emotional processes [7, 8].
It also appears that the same neuropeptides and trans-mitters (including opioids and dopamine) which are known to control appetite and satiety [9], also mediate "reward" processes in the brain (for example, the satis¬faction following natural rewarding stimuli such as food, sexual activity or artificial rewarding stimuli such as recreational drugs). Thus, the common basis for food intake and the feeling of reward/satisfaction probably explains the rewarding qualities of food in¬gestion.
The ECBR (endocannabinoid CB receptor) system and alimentary control
The ECBR system, consisting of the cannabinoid (CB1 and CB2) receptors and their endogenous activating ligands, the 'endocannabinoids' (mainly anandamide and 2-arachidonoyl glycerol, 2AG) and their synthesiz¬ing and degrading enzymes and putative reuptake transporters [4, 10, 11], is fully functional in the nerv¬ous system, in the GI system as well as in fat cells [12, 13].
Nervous system
Components of the ECBR system are present in most structures throughout the brain [4, 14], including one of the dopamine-carrying neural pathways, the 'mesolim¬bic system' [10]. As mentioned above, the incentive, pleasurable value of food is apparently controlled by this "reward" system. Not surprisingly then, the endo¬cannabinoid 2AG directly administered to this system, induced the intake of exaggerated amounts of food (hyperphagia) [15]. These and similar findings strongly suggest a role for the ECBR system in regulating food intake through the incentive value of food [10].
A role for the ECBR system in the ability to cope with stress has been studied using behavioral and biochemi¬cal [16-18] techniques. As outlined above, stress strongly influences both feeding and digestion. There-fore, the ECBR system may be expected to exert part of its influence on alimentary control through its influ¬ence on the stress-regulating physiological systems.
In addition to the influence of the ECBR system on feeding, appetite and digestion through the reward- and the stress-regulating systems, the cannabinoids influence feeding and digestion by interacting with a num-ber of additional alimentary control hormones, includ¬ing the appetite-inducing (orexigenic) ghrelin hormone [19] and the appetite reducing hormone leptin [20].
In the lower parts of the brain (the hindbrain), a num-ber of small structures (the 'area postrema', 'nucleus of the solitary tract' and 'dorsal motor nucleus of the vagus') form the dorsal vagal complex, from where nausea and vomiting as well as muscle control of the oesophagus, is controlled. The presence of CB1 and recently, CB2 receptors in the dorsal vagal complex, have been demonstrated; functionally, they have been shown to regulate nausea and vomiting [21-23], inhibi¬tion of gastric motility [24] and gastric acid secretion [21]. Thus it is clear now, how cannabinoids including the plant-derived THC (dronabinol) or synthetic na¬bilone, exert their antiemetic effects, as seen in their administration to patients undergoing chemotherapy.
CB1 receptors are also present in the peripheral vagus nerve, on the afferent nerve endings in the gut. There, when activated, they influence the brain's perception of intestinal activity [21, 22], thus participating in the feedback loop from the gut to the brain.
Interestingly, activating CB1 and CB2 receptors which are found in the saliva of rats, reduced saliva secretion [25]. Thus it seems that that CB receptors play a role in alimentory control starting with the initial stage of the digestive process.
Gastrointestinal tract
CB1 receptors are located in the lower sphincter muscle of the oesophageal (LOS) [21]. Cannabinoid receptor activating ligands ('9-THC, WIN 55,212-2) inhibited the relaxation of this muscle in ferrets and dogs, there-by counteracting gastroesophageal acid reflux [22, 26], suggesting that cannabinoid-based drugs may be useful therapeutics in the condition of gastroesophageal acid reflux.
CB1 are present throught the gastrointestinal tract [27, 28]. However in the colon (upper large intestine) and the stomach the densities are the highest. [29, 30]. Some of the CB1 receptors were found in the same neuronal cells as those containing the appetite and digestion-regulating hormones 'vasointestinal peptide and 'neuropetide Y' (VIP and NPY) [31], thus sug-gesting that the endocannabinoid cooperate with these hormones in controlling the gastrointestinal tract.
Thus the ubiquitous presence of the ECBR system in the GI system is supportive of the suggestion that the endocannabinoids and their receptors play a highly influential role in numerous key aspects of digestion. Indeed experiments have shown an effect of the ECBR system on secretory activity and motility of the gut [27]; it promotes inhibition of gastric emptying [32] and intestinal motility and food transit through the intestines [33-3 5]. Additional experiments have de¬monstrated a protective role for the ECBR system against inflammation of the GI system, for instance, in a mouse model for colitis [36].
A role for CB2 receptors in gastrointestinal activity was only recently fully accepted. An earlier report on CB2-mediated effects (by the CB2-selective agonist HU-308) on defecation in mice [37], was followed by many negative reports on a role for CB2 receptors in GI func¬tions [27, 28, 38]. However, CB2 receptors have now been demonstrated in the stomach [30] and in the in¬testines [39]. Although the issue needs further clarifi¬cation, the accompanying commentary to the report by Mathison and colleagues was aptly entitled "Cannabi¬noids and intestinal motility: welcome to CB2 receptor" [38].
Experiments have demonstrated that the endocannabi¬noids, as well as the degrading enzymes and uptake transporters [33, 40, 41] are present in the GI tract; the endocannabinoids at several-fold higher concentrations than in the brain [33, 42] and are physiologically active [40]. Anandamide-induced inhibition of defecation in mice was the first report that endocannabinoids in¬fluence intestinal function [43]. Thus the ECBR system appears to be highly important in the GI tract, probably playing a major role in digestion.
Adipose tissue
Di Marzo, Kunos and colleagues showed for the first time a link between leptin, the hormone originating in fat tissue which enters the brain to attenuate food in-take, and the ECBR system [44]. Thus leptin injection to rats reduced the concentrations of the endocannabi¬noids anandamide and 2AG [20]; anandamide and 2AG in turn, stimulate appetite and food intake. Conversely, specific mutations of mice and rats which are obese due to inherent deficiencies of the leptin system, dis¬played elevated levels of endocannabinoids [20] thus explaining their exaggerated food intake. Importantly, leptin was found to enhance the activity of the endo¬cannabinoid degrading enzyme FAAH (fatty acid am¬ide hydroxylase), by up-regulating the expression of the FAAH gene at the promotor level [45], thereby explaining the underlying mechanism of the leptin-endocannabioid negative balance reported earlier [20]. CB1 receptors have also been detected in animal adi¬pose (fat) tissue [46-48], while the full set of ECBR system components (CB1 and CB2 receptors, anan¬damide and 2AG, synthesizing and degrading en¬zymes) has recently also been described in human adipose cells [13, 49]. Importantly, CB1 receptors are dysregulated in human abdominal obesity [47].
Concluding this section, it is clear that every level of the alimentary system is affected by the ECBR system. In addition to the organ systems discussed here, and beyond the scope of the present review, organs such as the liver [50] and the pancreas [51] may also be in¬volved in this intricate network. Strikingly, ECBR influence on ingestion, digestion and emesis is always, at the organismic level, in harmony (see also Table 1). Thus (endo)cannabinoids reduce intestinal and gastric motility, gastric acid secretion, emesis and nausea, are anti-diarrheal and enhance appetite. Conversely, CB 1 receptor blocking agents (antagonists) cause emesis, anorexia and enhanced motility. This unified activity makes the ECBR system exquisitely suitable for multi-leveled treatment of digestive and appetite-related syndromes such as irritable bowel syndrome and cachexia/anorexia, using ECBR-activating agents [21] or obesity/metabolic syndrome, using ECBR-inhibitors [52].
The ECBR system in pathophysiological and psy¬chosomatic conditions of ingestion and digestion
The ECBR system, as described above, is strongly represented in brain, GI tract and adipose tissue. Espe¬cially its involvement in emotional processing makes the ECBR system an excellent candidate as an underly¬ing factor in the pathology of psychosomatic problems of the digestive system as well as a target for new the¬rapeutic approaches.
Irritable bowel syndrome (IBS). Solid evidence exists for an (endo)cannabinoid-regulated reduction of intestinal motility [40, 43, 53, 54] through CB1 [33] and CB2 [39, 43, 55] receptors. This property of the ECBR system has been proposed to be beneficial for IBS which is often characterized by enhanced intestinal motility and contractility [40, 41].
Inflammatory bowel disease (IBD). Inflammatory bowel diseases, including Crohn's disease and ulcerati¬ve colitis, result from inflammatory processes in the intestine and are characterized by ulcers, rectal blee¬ding diarrhea, nausea and lack of appetite [41]. As stated above, the importance of CB1 receptors in protecting the organism against inflammation of the GI system was demonstrated in an animal study for expe¬rimentally-induced colitis [36]. In an animal model for Crohn's disease, a beneficial, slowing effect of endo¬cannabinoids on intestinal motility has been de¬monstrated [33, 34]. This effect was apparently media¬ted by CB receptors in the gut (and not via the brain). Therefore cannabinoid-based treatment is promising when psychological approaches are not likely to be helpful.
Gastroesophageal reflux disease (GORD). This di-sorder results from a weak lower oesophagal sphincter muscle causing gastric content to flow upward, hence symptoms including heartburn and acid regurgitation appear [41, 56]. The influence of psychological stress, anxiety and depression on this condition has been shown [56-58]. Cannabinoid-based therapies may be developed, acting through cannabinoid receptors in the brain or through peripheral neural control. Indeed, cannabinoid CB1 receptor agonists have been shown to relax the oesophageal sphincter in dogs and ferrets; this effects was mediated by cannabinoid receptors on the vagus nerve at peripheral as well as central sites [22, 26, 27].
Secretory diarrhea. Fluid-induced increase in stool volume, that is, secretory diarrhea, is caused by ab-normal and/or absorption of water and electrolytes as well as dysregulated intestinal motility [59, 60]. Psy-chological stress may precipitate secretory diarrhea. This occurs probably when stress induces the activati¬on of receptors for corticotrophin releasing hormone (CRH1) [60]. Several studies have demonstrated the role of the ECBR system in this process. Thus, stimula¬tion of the ECBR system reduced intestinal fluid ac-cumulation; conversely, the blocking CB1 receptors with the antagonist rimonabant increased fluid accumu¬lation [27]. These observations suggest that the endo¬cannabinoids exert a tonic regulation of intestinal sec¬retory activity which can be up-or down-regulated according to the (psycho)physiological environment. Further, since cannabinoid CB1 receptor activation resulted in decreased fluid accumulation in the small intestine of the rat, cannabinoid-based treatment may be beneficial for diarrhea [61].
Gastric ulcer. The formation of gastric ulcers is known to be stimulated by psychological stress. The ability of cannabinoids to reduce gastric secretions and ulcer formation has been observed many years ago. Interestingly, cannabinoids reduced ulcers which had been caused by stress [62]. This effect may have been achieved by direct activation of cannabinoid receptors in the stomach or by reducing the stress reponse [30] in the central nervous system [63], or by both mecha¬nisms.
Emesis. Antiemetic effects of (endo)cannabinoids have been extensively demonstrated as described above and several '9-THC (dronabinol) or THC-like cannabinoid drugs (the synthetic nabilone) are selectively available for oral clinical use [27, 41, 64, 65]. The antiemetic
effects are mediated by CB1 and CB2 receptors located on gastric vagal nerves or via lower brain structures of the dorsal vagal complex [27, 66]. Taken together, it is widely agreed that CB-based drugs, especially those which do not have central side effects, should be deve¬loped as antiemetic drugs for cancer and AIDS patients who receive chemotherapeutic treatment. Cannabinoids may be especially effective in combating anticipatory nausea and vomiting [67]. Since the area postrema has receptors located outside the brain, CB1 receptor-specific cannabinoids which are not active within the CNS, should be particularly suitable [68, 69].
Neonatal milk intake
Although perhaps one of the major physiological sys-tems (see also Table 1), the ECBR system does not seem critical for survival. Thus for example, the majo¬rity of mice which genetically lack CB1 and/or CB2 receptors, survive into adulthood, albeit with reduced body weights [70-72]. Similarly, very long term treat¬ment (4 months) with the CB1 receptor antagonist ri¬monabant did not cause mortality or (overt) detrimental effects, except for a robust reduction in body weight [73]. In contrast, we have shown that a single injection with rimonabant administered to newborn mice within 24 h of birth, interferes with milk ingestion; this in turn resulted in growth failure and death in many cases. Further investigation into the sequelae of neonatal rimonabant-treatment suggested that CB1 receptor activation in neonates is required for oral-motor deve¬lopment required for sucking [74]. Since the behavioral and physiological deficiencies of CB1 receptor-blocked mouse pups resemble infants suffering from "non-organic failure-to-thrive" (NOFTT), we have suggested that CB1 receptor-blocked neonates may be used as a model for NOFTT and form the basis for the develop¬ment of cannabinoid-based treatments.
Conclusions and future directions
Three major conclusions emanate from the material reviewed here: (i) the ECBR system is a of major me-diating system between the brain, the alimentary sys-tem and the adipose tissue, (ii) it is speculated that the role of the ECBR system in adult regulation of digesti¬on and ingestion may be a remnant of their critical role for the initiation of feeding and survival in the new-born, and (iii) the pervasive influence of the ECBR system in alimentary control, make it a highly suitable target for therapeutic developments aimed at allevia¬ting pathophysiological conditions such as inflammato¬ry bowel disease (IBD), irritable bowel syndrome (IBS), gastric ulcers, nausea, anorexia and obesity.
The CB1 receptor, rather than the CB2 receptor, seems to be the major mediator of ECBR control of the gas-trointestinal tract and food intake, and should therefore be the main target of therapeutic cannabinoid-based drugs. However CB1 receptor agonists often have undesirable psychoactive effects such as confusion and anxiety. We have recently demonstrated that several (+)cannabidiol derivates [such as (+)cannabidiol-demethyl heptyl and (+)carboxy-cannabidiol-demethyl heptyl], displayed CB1-receptor mediated inhibition of intestinal motility in the absence of psychoactive ef¬fects [68, 69]. Further, upregulating the ECBR system by the inhibition of enzymatic breakdown or reuptake inhibition, is expected to yield more selective therapeu¬tic effects, since the manipulation of ECBR function would be restricted to the anatomical sites which are activated at that moment. Preventing endocannabinoid degradation with oleamide, a fatty acid amide which is considered by most [75-78] not to bind CB1 receptors, resulted in psychoactive effects similar to those of anandamide itself [75]. On the other hand, URB597, the highly selective inhibitor of the FAAH enzyme responsible for endocannabinoid breakdown, is thought to have anxiolytic and antidepressant potential without sedative and addictive properties [79]. Thus this or similar FAAH inhibitors may also be useful for the treatment of digestive and ingestive dysfunctions without undesirable psychoactive side effects.
Acknowledgments
This work was supported in part by a grant from San-ofi-Aventis (France) and by intramural support from the College of Judea and Samaria.
References
1. Jones MP, Dilley JB, Drossman D, Crowell MD. Brain-gut connections in functional GI disorders: anatomic and physiologic relationships. Neuro-gastroenterol Motil. 2006; 18:91-103.
2. Konturek SJ, Konturek JW, Pawlik T, Brzo-zowski T. Brain-gut axis and its role in the con-trol of food intake. J Physiol Pharmacol. 2004;55:137-54.
3. Ringel Y. New directions in brain imaging re-search in functional gastrointestinal disorders. Dig Dis. 2006;24:278-85.
4. Fride E. Endocannabinoids in the central nervous system: from neuronal networks to behavior. Curr Drug Targets CNS Neurol Disord. 2005;4:633-42.
5. Strader AD, Woods SC. Gastrointestinal hor-mones and food intake. Gastroenterology. 2005; 128: 175-91.
6. Zhang DM, Bula W, Stellar E. Brain chole-cystokinin as a satiety peptide. Physiol Behav. 1986;36:1 183-6.
7. Shumyatsky GP, Tsvetkov E, Malleret G, Vron-skaya S, Hatton M, Hampton L, Battey JF, Dulac
C, Kandel ER, Bolshakov VY. Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically re-lated to learned fear. Cell. 2002; 111:905-18.
8. Lago F, Gonzalez-Juanatey JR, Casanueva FF, Gomez-Reino J, Dieguez C, Gualillo O. Ghrelin, the same peptide for different functions: player or bystander? Vitam Horm. 2005;71 :405-32.
9. Volkow ND, Wang GJ, Maynard L, Jayne M, Fowler JS, Zhu W, Logan J, Gatley SJ, Ding YS, Wong C, Pappas N. Brain dopamine is associated with eating behaviors in humans. Int J Eat Dis¬ord. 2003;33:136-42.
10. Fride E, Bregman T, Kirkham TC. Endocannabi-noids and food intake: newborn suckling and ap-petite regulation in adulthood. Exp Biol Med (Maywood). 2005;230:225-34.
11. Mechoulam R, Hanus L, Fride E. Towards can-nabinoid drugs--revisited. Prog Med Chem. 1998;35:199-243.
12. Matias I, Gonthier MP, Orlando P, Martiadis V, De Petrocellis L, Cervino C, Petrosino S, Hoareau L, Festy F, Pasquali R, Roche R, Maj M, Pagotto U, Monteleone P, Di Marzo V. Regula¬tion, function, and dysregulation of endocannabi¬noids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab. 2006;91:3171-80.
13. Spoto B, Fezza F, Parlongo G, Battista N, Sgro E, Gasperi V, Zoccali C, Maccarrone M. Human adipose tissue binds and metabolizes the endo-cannabinoids anandamide and 2-arachidonoylglycerol. Biochimie. 2006;88: 1889-97.
14. Howlett AC, Breivogel CS, Childers SR, Dead-wyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of pro-gress. Neuropharmacology. 2004;47 Suppl 1:345-58.
15. Kirkham TC, Williams CM, Fezza F, Di Marzo V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol. 2002; 136:550-7.
16. Fride E, Suris R, Weidenfeld J, Mechoulam R. Differential response to acute and repeated stress in cannabinoid CB 1 receptor knockout newborn and adult mice. Behav Pharmacol. 2005; 16:431 - 40.
17. Patel S, Cravatt BF, Hillard CJ. Synergistic inter-actions between cannabinoids and environmental stress in the activation of the central amygdala. Neuropsychopharmacology. 2005;30:497-507.
18. Hill MN, Gorzalka BB. Increased sensitivity to restraint stress and novelty-induced emotionality following long-term, high dose cannabinoid ex-posure. Psychoneuroendocrinology. 2006;3 1:526-36.
19. Tucci SA, Rogers EK, Korbonits M, Kirkham TC. The cannabinoid CB 1 receptor antagonist SR141 716 blocks the orexigenic effects of intra-hypothalamic ghrelin. Br J Pharmacol. 2004; 143 :520-3.
20. Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G. Leptin-regulated endocannabi-noids are involved in maintaining food intake. Nature. 2001 ;410:822-5.
21. Hornby PJ, Prouty SM. Involvement of cannabi-noid receptors in gut motility and visceral percep¬tion. Br J Pharmacol. 2004;141 :1335-45.
22. Partosoedarso ER, Abrahams TP, Scullion RT, Moerschbaecher JM, Hornby PJ. Cannabinoid1 receptor in the dorsal vagal complex modulates lower oesophageal sphincter relaxation in ferrets. J Physiol. 2003;550:149-58.
23. Van Sickle MD, Oland LD, Mackie K, Davison JS, Sharkey KA. Delta9-tetrahydrocannabinol se-lectively acts on CB 1 receptors in specific re-gions of dorsal vagal complex to inhibit emesis in ferrets. Am J Physiol Gastrointest Liver Physiol. 2003;285:G566-76.
24. Krowicki ZK, Moerschbaecher JM, Winsauer PJ, Digavalli SV, Hornby PJ. Delta9-tetrahydrocannabinol inhibits gastric motility in the rat through cannabinoid CB 1 receptors. Euro¬pean journal of pharmacology. 1 999;371 :187-96.
25. Prestifilippo JP, Fernandez-Solari J, de la Cal C, Iribarne M, Suburo AM, Rettori V, McCann SM, Elverdin JC. Inhibition of salivary secretion by activation of cannabinoid receptors. Exp Biol Med (Maywood). 2006;231:1421-9.
26. Lehmann A, Blackshaw LA, Branden L, Carlsson A, Jensen J, Nygren E, Smid SD. Cannabinoid receptor agonism inhibits transient lower eso¬phageal sphincter relaxations and reflux in dogs. Gastroenterology. 2002; 123:1129-34.
27. Coutts AA, Izzo AA. The gastrointestinal phar-macology of cannabinoids: an update. Curr Opin Pharmacol. 2004;4:572-9.
28. Pertwee RG. Cannabinoids and the gastrointesti-nal tract. Gut. 2001 ;48:859-67.
29. Casu MA, Porcella A, Ruiu S, Saba P, Marchese G, Carai MA, Reali R, Gessa GL, Pani L. Differ-ential distribution of functional cannabinoid CB1 receptors in the mouse gastroenteric tract. Euro-pean journal of pharmacology. 2003;459:97-1 05.
30. Adami M, Frati P, Bertini S, Kulkarni-Narla A, Brown DR, de Caro G, Coruzzi G, Soldani G. Gastric antisecretory role and immunohisto-chemical localization of cannabinoid receptors in the rat stomach. Br J Pharmacol. 2002; 135:1598-606.
31. Coutts AA, Irving AJ, Mackie K, Pertwee RG, Anavi-Goffer S. Localisation of cannabinoid CB(1) receptor immunoreactivity in the guinea pig and rat myenteric plexus. J Comp Neurol. 2002;448:410-22.
32. Landi M, Croci T, Rinaldi-Carmona M, Maffrand JP, Le Fur G, Manara L. Modulation of gastric emptying and gastrointestinal transit in rats through intestinal cannabinoid CB(1) receptors. European journal of pharmacology. 2002;450:77-83.
33. Izzo AA, Fezza F, Capasso R, Bisogno T, Pinto
L, Iuvone T, Esposito G, Mascolo N, Di Marzo V, Capasso F. Cannabinoid CB1-receptor medi-ated regulation of gastrointestinal motility in mice in a model of intestinal inflammation. Br J Pharmacol. 2001; 134:563-70.
34. Izzo AA, Pinto L, Borrelli F, Capasso R, Mascolo N, Capasso F. Central and peripheral cannabinoid modulation of gastrointestinal transit in physio¬logical states or during the diarrhoea induced by croton oil. Br J Pharmacol. 2000;129:1627-32.
35. Manara L, Croci T, Guagnini F, Rinaldi-Carmona
M, Maffrand JP, Le Fur G, Mukenge S, Ferla G. Functional assessment of neuronal cannabinoid receptors in the muscular layers of human ileum and colon. Dig Liver Dis. 2002;34:262-9.
36. Massa F, Marsicano G, Hermann H, Cannich A, Monory K, Cravatt BF, Ferri GL, Sibaev A, Storr M, Lutz B. The endogenous cannabinoid system protects against colonic inflammation. J Clin In-vest. 2004;1 13:1202-9.
37. Hanus L, Abu-Lafi S, Fride E, Breuer A, Vogel Z, Shalev DE, Kustanovich I, Mechoulam R. 2-arachidonyl glyceryl ether, an endogenous ago¬nist of the cannabinoid CB 1 receptor. Proc Natl Acad Sci U S A. 2001;98:3662-5.
38. Izzo AA. Cannabinoids and intestinal motility: welcome to CB2 receptors. Br J Pharmacol. 2004; 142: 1201-2.
39. Mathison R, Ho W, Pittman QJ, Davison JS, Sharkey KA. Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats. Br J Pharma-col. 2004;142:1247-54.
40. Pinto L, Izzo AA, Cascio MG, Bisogno T, Hospodar-Scott K, Brown DR, Mascolo N, Di Marzo V, Capasso F. Endocannabinoids as physiological regulators of colonic propulsion in mice. Gastroenterology. 2002; 123:227-34.
41. Di Carlo G, Izzo AA. Cannabinoids for gastroin-testinal diseases: potential therapeutic applica-tions. Expert Opin Investig Drugs. 2003;12:39-49.
42. Pinto L, Capasso R, Di Carlo G, Izzo AA. Endo-cannabinoids and the gut. Prostaglandins Leukot Essent Fatty Acids. 2002;66:333-41.
43. Fride E. Anandamides: tolerance and cross-tolerance to delta 9-tetrahydrocannabinol. Brain Res. 1995;697:83-90.
44. Mechoulam R, Fride E. Physiology. A hunger for cannabinoids. Nature. 2001 ;410:763, 5.
45. Maccarrone M, Di Rienzo M, Finazzi-Agro A, Rossi A. Leptin activates the anandamide hy-drolase promoter in human T lymphocytes through STAT3. The Journal of biological chem-istry. 2003;278:133 18-24.
46. Bensaid M, Gary-Bobo M, Esclangon A, Maf-frand JP, Le Fur G, Oury-Donat F, Soubrie P. The cannabinoid CB 1 receptor antagonist
SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cul-tured adipocyte cells. Mol Pharmacol. 2003;63:908-14.
47. Bluher M, Engeli S, Kloting N, Berndt J, Fasshauer M, Batkai S, Pacher P, Schon MR, Jordan J, Stumvoll M. Dysregulation of the pe-ripheral and adipose tissue endocannabinoid sys¬tem in human abdominal obesity. Diabetes. 2006;55:3053-60.
48. Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thone-Reineke C, Ortmann S, Tomassoni F, Cervino C, Nisoli E, Linthorst AC, Pasquali R, Lutz B, Stalla GK, Pagotto U. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogene¬sis. J Clin Invest. 2003;112:423-31.
49. Roche R, Hoareau L, Bes-Houtmann S, Gonthier MP, Laborde C, Baron JF, Haffaf Y, Cesari M, Festy F. Presence of the cannabinoid receptors, CB1 and CB2, in human omental and subcutane-ous adipocytes. Histochem Cell Biol. 2006; 126:177-87.
50. Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Batkai S, Harvey-White J, Mackie K, Offertaler L, Wang L, Kunos G. Endocannabi-noid activation at hepatic CB 1 receptors stimu-lates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115:1298-305.
51. Pagotto U, Vicennati V, Pasquali R. The endo-cannabinoid system in the physiopathology of metabolic disorders. Horm Res. 2007;67 Suppl 1:186-90.
52. Wierzbicki AS. Rimonabant: endocannabinoid inhibition for the metabolic syndrome. Int J Clin Pract. 2006;60: 1697-706.
53. Fride E, Mechoulam R. Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. European journal of pharma¬cology. 1993;231 :313-4.
54. Pertwee RG, Fernando SR, Nash JE, Coutts AA. Further evidence for the presence of cannabinoid CB1 receptors in guinea-pig small intestine. Br J Pharmacol. 1996;1 18:2199-205.
55. Hanus L, Breuer A, Tchilibon S, Shiloah S, Goldenberg D, Horowitz M, Pertwee RG, Ross RA, Mechoulam R, Fride E. HU-308: a specific agonist for CB(2), a peripheral cannabinoid re-ceptor. Proc Natl Acad Sci U S A. 1999;96:14228-33.
56. Fass R, Ofman JJ. Gastroesophageal reflux dis-ease--should we adopt a new conceptual frame-work? Am J Gastroenterol. 2002;97: 1901-9.
57. Wright CE, Ebrecht M, Mitchell R, Anggiansah A, Weinman J. The effect of psychological stress on symptom severity and perception in patients with gastro-oesophageal reflux. J Psychosom Res. 2005;59:41 5-24.
58. Richter JE, Bradley LC. Psychophysiological interactions in esophageal diseases. Semin Gas-trointest Dis. 1996;7:169-84.
59. Sanger GJ, Yoshida M, Yahyah M, Kitazumi K. Increased defecation during stress or after 5-hydroxytryptophan: selective inhibition by the 5-HT(4) receptor antagonist, SB-207266. Br J Pharmacol. 2000; 130:706-12.
60. Saunders PR, Maillot C, Million M, Tache Y. Peripheral corticotropin-releasing factor induces diarrhea in rats: role of CRF1 receptor in fecal watery excretion. European journal of pharma-cology. 2002;43 5:231-5.
61. Tyler K, Hillard CJ, Greenwood-Van Meerveld B. Inhibition of small intestinal secretion by can-nabinoids is CB1 receptor-mediated in rats. European journal of pharmacology. 2000;409:207-1 1.
62. Germano MP, D'Angelo V, Mondello MR, Per-golizzi S, Capasso F, Capasso R, Izzo AA, Mas-colo N, De Pasquale R. Cannabinoid CB 1-mediated inhibition of stress-induced gastric ul¬cers in rats. Naunyn Schmiedebergs Arch Phar¬macol. 2001 ;363 :241-4.
63. Patel S, Roelke CT, Rademacher DJ, Cullinan WE, Hillard CJ. Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis. Endocri¬nology. 2004;145:5431-8.
64. Darmani NA. Methods evaluating cannabinoid and endocannabinoid effects on gastrointestinal functions. Methods Mol Med. 2006; 123:169-89.
65. Parker LA, Kwiatkowska M, Burton P, Mechou-lam R. Effect of cannabinoids on lithium-induced vomiting in the Suncus murinus (house musk shrew). Psychopharmacology (Berl). 2004;171:156-61.
66. Van Sickle MD, Duncan M, Kingsley PJ, Moui-hate A, Urbani P, Mackie K, Stella N, Makriyan-nis A, Piomelli D, Davison JS, Marnett LJ, Di Marzo V, Pittman QJ, Patel KD, Sharkey KA. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005;3 10:329-32.
67. Parker LA, Kemp SW. Tetrahydrocannabinol (THC) interferes with conditioned retching in Suncus murinus: an animal model of anticipatory nausea and vomiting (ANV). Neuroreport. 2001; 12:749-51.
68. Fride E, Feigin C, Ponde DE, Breuer A, Hanus L, Arshavsky N, Mechoulam R. (+)-Cannabidiol analogues which bind cannabinoid receptors but exert peripheral activity only. European journal of pharmacology. 2004;506: 179-88.
69. Fride E, Ponde D, Breuer A, Hanus L. Peripheral, but not central effects of cannabidiol derivatives: Mediation by CB(1) and unidentified receptors. Neuropharmacology. 2005;48:1 117-29.
70. Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F, Bohme GA, Imperato A, Pedrazzini T, Roques BP, Vassart G, Fratta W, Parmentier
M. Unresponsiveness to cannabinoids and re-duced addictive effects of opiates in CB1 receptor knockout mice. Science. 1999;283:401-4.
71. Zimmer A, Zimmer AM, Hohmann AG, Herken-ham M, Bonner TI. Increased mortality, hypoac-tivity, and hypoalgesia in cannabinoid CB 1 re-ceptor knockout mice. Proc Natl Acad Sci U S A. 1999;96:5780-5.
72. Paria BC, Song H, Wang X, Schmid PC, Krebs-bach RJ, Schmid HH, Bonner TI, Zimmer A, Dey SK. Dysregulated cannabinoid signaling disrupts uterine receptivity for embryo implantation. The Journal of biological chemistry. 2001 ;276:20523-8.
73. Gobshtis N, Ben-Shabat S, Fride E. Antidepres-sant-induced undesirable weight gain: prevention with rimonabant without interference with behav¬ioral effectiveness. European journal of pharma¬cology. 2007;554:1 55-63.
74. Fride E, Peretz-Ezra D, Arshavsky N, H D, Weller A. The CB 1 receptor and "non-organic failure-to thrive" in infants: the first animal (mouse) model. 33rd Annual Meeting of the So¬ciety for Neuroscience Washington DC, USA. 2005.
75. Mechoulam R, Fride E, Hanus L, Sheskin T, Bisogno T, Di Marzo V, Bayewitch M, Vogel Z. Anandamide may mediate sleep induction. Na-ture. 1997;389:25-6.
76. Sheskin T, Hanus L, Slager J, Vogel Z, Mechou-lam R. Structural requirements for binding of an-andamide-type compounds to the brain cannabi-noid receptor. J Med Chem. 1997;40:659-67.
77. Fowler CJ. Oleamide: a member of the endocan-nabinoid family? Br J Pharmacol. 2004;141 :195-6.
78. Leggett JD, Aspley S, Beckett SR, D'Antona AM, Kendall DA, Kendall DA. Oleamide is a selective endogenous agonist of rat and human CB 1 can-nabinoid receptors. Br J Pharmacol. 2004;141 :253-62.
79. Piomelli D, Tarzia G, Duranti A, Tontini A, Mor M, Compton TR, Dasse O, Monaghan EP, Parrott JA, Putman D. Pharmacological profile of the se-lective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev. 2006;12:21-38.
80. Parker LA, Mechoulam R, Schlievert C, Abbott L, Fudge ML, Burton P. Effects of cannabinoids on lithium-induced conditioned rejection reac¬tions in a rat model of nausea. Psychopharmacol¬ogy (Berl). 2003;166:156-62.
Source: The endogenous cannabinoid system: a new player in the brain-gut-adipose axis
College of Judea and Samaria, Departments of Behavioral Sciences and Molecular Biology, Ariel, Israel
Abstract
The 'endocannabinoid (CB) receptor (ECBR) system', consists of specific receptors and several endogenous ligands. The ECBR system is involved in many physiological functions including immunity, inflammation, neurotoxicity and neurotrauma, epilepsy, depression and stress, appetite, food intake and energy homeostasis, cardiovascular regulation, reproduction, and bone remode¬ling. The brain and gastrointestinal system interact bidirectionally in the regulation of digestive processes, food ingestion and energy balance (hence the 'brain-gut axis'). Emotional stress and and the 'reward' center in the brain modulate the brain-gut axis. ECBR presence in brain, gastroin¬testinal as well as adipose (fat) tissue as well as its involvement in stress and emotional processing, provide it with a major role in food intake, digestion and the regulation of adipose tissue mass and adipocyte endocrine function. With cannabinoid receptors and endocannabinoids present from the early embryonic stages and in maternal milk, the ECBR system seems of critical value for new-born milk ingestion.
It is concluded that (i) the ECBR system is a major mediator between the brain and the digestive system, (ii) the role of the ECBR system in adult regulation of food processing is a remnant of its critical role for the initiation of feeding in the newborn, and (iii) the pervasive influence of the ECBR system in alimentary control, make it a highly suitable target for therapeutic developments for conditions such as inflammatory bowel disease, irritable bowel syndrome, gastric ulcers, nau¬sea, obesity, anorexia and failure-to-thrive.
Key words: CB1, CB2, development, feeding, appetite, gastrointestinal tract, adipose tissue
This article can be downloaded, printed and distributed freely for any non-commercial purposes, provided the original work is prop¬erly cited (see copyright info below). Available online at cannabis medicine
Author's address: Ester Fride, fride@yosh.ac.il
Introduction: the "alimentary control system"
Appetite, hunger and satiety are regulated by a number of hormonal signals emanating from the central ner¬vous system (CNS) and gastrointestinal (GI) tract [1, 2]. It is impossible to separate the appetite-hunger¬satiety signals which regulate food intake, from the digestive processes in the GI tract and secretions from adipose (fat) tissue such as the hormone leptin. There-fore in this review, regulation of food intake, appetite and the brain-gut-adipose system will be considered as one system regulating ingestion and digestion, and will be denoted the "alimentary control system".
The rich bidirectional interactions between the brain and the local neuronal network (the enteric nervous
© International Association for Cannabis as Medicine
system - ENS) in the intestinal system (the 'brain-gut axis'), have been extensively studied. Thus, for e - xample, psychological stress has been shown to affect gut activities such as secretion and motility [3]. Con¬versely, using brain imaging techniques such as func¬tional magnetic resonance imaging (fMRI) or positron emission tomography (PET), it has been demonstrated that visceral sensation resulting from stimulation of the oesophagus, stomach or rectum, resulted in activation of higher brain centers including the somatosensory cortex, thalamus and prefrontal cortex [3].
Ingestion and digestion are controlled by a large num¬ber of hormones which originate from the brain, GI tract and adipose tissue and which act in as a signaling network of mutual influence. The major hormones
include leptin (from adipose tissue), cholecystokinin (CCK), peptide tyrosine (PYY) and orexin A and B [2, 4-6].
Emotional stress and reward
Interestingly, the major hormones (such as corticotro-phic releasing hormone (CRH)) and brain structures involved in modulating emotional and stress responses (such as the hypothalamus and the amygdala) are also important modulators of gastrointestinal tract activity such as GI motility and gastric emptying [1]. Conver¬sely, hormones associated with gastrointestinal functi¬oning such as the gastrin-releasing peptide (GRP), and ghrelin, affect emotional processes [7, 8].
It also appears that the same neuropeptides and trans-mitters (including opioids and dopamine) which are known to control appetite and satiety [9], also mediate "reward" processes in the brain (for example, the satis¬faction following natural rewarding stimuli such as food, sexual activity or artificial rewarding stimuli such as recreational drugs). Thus, the common basis for food intake and the feeling of reward/satisfaction probably explains the rewarding qualities of food in¬gestion.
The ECBR (endocannabinoid CB receptor) system and alimentary control
The ECBR system, consisting of the cannabinoid (CB1 and CB2) receptors and their endogenous activating ligands, the 'endocannabinoids' (mainly anandamide and 2-arachidonoyl glycerol, 2AG) and their synthesiz¬ing and degrading enzymes and putative reuptake transporters [4, 10, 11], is fully functional in the nerv¬ous system, in the GI system as well as in fat cells [12, 13].
Nervous system
Components of the ECBR system are present in most structures throughout the brain [4, 14], including one of the dopamine-carrying neural pathways, the 'mesolim¬bic system' [10]. As mentioned above, the incentive, pleasurable value of food is apparently controlled by this "reward" system. Not surprisingly then, the endo¬cannabinoid 2AG directly administered to this system, induced the intake of exaggerated amounts of food (hyperphagia) [15]. These and similar findings strongly suggest a role for the ECBR system in regulating food intake through the incentive value of food [10].
A role for the ECBR system in the ability to cope with stress has been studied using behavioral and biochemi¬cal [16-18] techniques. As outlined above, stress strongly influences both feeding and digestion. There-fore, the ECBR system may be expected to exert part of its influence on alimentary control through its influ¬ence on the stress-regulating physiological systems.
In addition to the influence of the ECBR system on feeding, appetite and digestion through the reward- and the stress-regulating systems, the cannabinoids influence feeding and digestion by interacting with a num-ber of additional alimentary control hormones, includ¬ing the appetite-inducing (orexigenic) ghrelin hormone [19] and the appetite reducing hormone leptin [20].
In the lower parts of the brain (the hindbrain), a num-ber of small structures (the 'area postrema', 'nucleus of the solitary tract' and 'dorsal motor nucleus of the vagus') form the dorsal vagal complex, from where nausea and vomiting as well as muscle control of the oesophagus, is controlled. The presence of CB1 and recently, CB2 receptors in the dorsal vagal complex, have been demonstrated; functionally, they have been shown to regulate nausea and vomiting [21-23], inhibi¬tion of gastric motility [24] and gastric acid secretion [21]. Thus it is clear now, how cannabinoids including the plant-derived THC (dronabinol) or synthetic na¬bilone, exert their antiemetic effects, as seen in their administration to patients undergoing chemotherapy.
CB1 receptors are also present in the peripheral vagus nerve, on the afferent nerve endings in the gut. There, when activated, they influence the brain's perception of intestinal activity [21, 22], thus participating in the feedback loop from the gut to the brain.
Interestingly, activating CB1 and CB2 receptors which are found in the saliva of rats, reduced saliva secretion [25]. Thus it seems that that CB receptors play a role in alimentory control starting with the initial stage of the digestive process.
Gastrointestinal tract
CB1 receptors are located in the lower sphincter muscle of the oesophageal (LOS) [21]. Cannabinoid receptor activating ligands ('9-THC, WIN 55,212-2) inhibited the relaxation of this muscle in ferrets and dogs, there-by counteracting gastroesophageal acid reflux [22, 26], suggesting that cannabinoid-based drugs may be useful therapeutics in the condition of gastroesophageal acid reflux.
CB1 are present throught the gastrointestinal tract [27, 28]. However in the colon (upper large intestine) and the stomach the densities are the highest. [29, 30]. Some of the CB1 receptors were found in the same neuronal cells as those containing the appetite and digestion-regulating hormones 'vasointestinal peptide and 'neuropetide Y' (VIP and NPY) [31], thus sug-gesting that the endocannabinoid cooperate with these hormones in controlling the gastrointestinal tract.
Thus the ubiquitous presence of the ECBR system in the GI system is supportive of the suggestion that the endocannabinoids and their receptors play a highly influential role in numerous key aspects of digestion. Indeed experiments have shown an effect of the ECBR system on secretory activity and motility of the gut [27]; it promotes inhibition of gastric emptying [32] and intestinal motility and food transit through the intestines [33-3 5]. Additional experiments have de¬monstrated a protective role for the ECBR system against inflammation of the GI system, for instance, in a mouse model for colitis [36].
A role for CB2 receptors in gastrointestinal activity was only recently fully accepted. An earlier report on CB2-mediated effects (by the CB2-selective agonist HU-308) on defecation in mice [37], was followed by many negative reports on a role for CB2 receptors in GI func¬tions [27, 28, 38]. However, CB2 receptors have now been demonstrated in the stomach [30] and in the in¬testines [39]. Although the issue needs further clarifi¬cation, the accompanying commentary to the report by Mathison and colleagues was aptly entitled "Cannabi¬noids and intestinal motility: welcome to CB2 receptor" [38].
Experiments have demonstrated that the endocannabi¬noids, as well as the degrading enzymes and uptake transporters [33, 40, 41] are present in the GI tract; the endocannabinoids at several-fold higher concentrations than in the brain [33, 42] and are physiologically active [40]. Anandamide-induced inhibition of defecation in mice was the first report that endocannabinoids in¬fluence intestinal function [43]. Thus the ECBR system appears to be highly important in the GI tract, probably playing a major role in digestion.
Adipose tissue
Di Marzo, Kunos and colleagues showed for the first time a link between leptin, the hormone originating in fat tissue which enters the brain to attenuate food in-take, and the ECBR system [44]. Thus leptin injection to rats reduced the concentrations of the endocannabi¬noids anandamide and 2AG [20]; anandamide and 2AG in turn, stimulate appetite and food intake. Conversely, specific mutations of mice and rats which are obese due to inherent deficiencies of the leptin system, dis¬played elevated levels of endocannabinoids [20] thus explaining their exaggerated food intake. Importantly, leptin was found to enhance the activity of the endo¬cannabinoid degrading enzyme FAAH (fatty acid am¬ide hydroxylase), by up-regulating the expression of the FAAH gene at the promotor level [45], thereby explaining the underlying mechanism of the leptin-endocannabioid negative balance reported earlier [20]. CB1 receptors have also been detected in animal adi¬pose (fat) tissue [46-48], while the full set of ECBR system components (CB1 and CB2 receptors, anan¬damide and 2AG, synthesizing and degrading en¬zymes) has recently also been described in human adipose cells [13, 49]. Importantly, CB1 receptors are dysregulated in human abdominal obesity [47].
Concluding this section, it is clear that every level of the alimentary system is affected by the ECBR system. In addition to the organ systems discussed here, and beyond the scope of the present review, organs such as the liver [50] and the pancreas [51] may also be in¬volved in this intricate network. Strikingly, ECBR influence on ingestion, digestion and emesis is always, at the organismic level, in harmony (see also Table 1). Thus (endo)cannabinoids reduce intestinal and gastric motility, gastric acid secretion, emesis and nausea, are anti-diarrheal and enhance appetite. Conversely, CB 1 receptor blocking agents (antagonists) cause emesis, anorexia and enhanced motility. This unified activity makes the ECBR system exquisitely suitable for multi-leveled treatment of digestive and appetite-related syndromes such as irritable bowel syndrome and cachexia/anorexia, using ECBR-activating agents [21] or obesity/metabolic syndrome, using ECBR-inhibitors [52].
The ECBR system in pathophysiological and psy¬chosomatic conditions of ingestion and digestion
The ECBR system, as described above, is strongly represented in brain, GI tract and adipose tissue. Espe¬cially its involvement in emotional processing makes the ECBR system an excellent candidate as an underly¬ing factor in the pathology of psychosomatic problems of the digestive system as well as a target for new the¬rapeutic approaches.
Irritable bowel syndrome (IBS). Solid evidence exists for an (endo)cannabinoid-regulated reduction of intestinal motility [40, 43, 53, 54] through CB1 [33] and CB2 [39, 43, 55] receptors. This property of the ECBR system has been proposed to be beneficial for IBS which is often characterized by enhanced intestinal motility and contractility [40, 41].
Inflammatory bowel disease (IBD). Inflammatory bowel diseases, including Crohn's disease and ulcerati¬ve colitis, result from inflammatory processes in the intestine and are characterized by ulcers, rectal blee¬ding diarrhea, nausea and lack of appetite [41]. As stated above, the importance of CB1 receptors in protecting the organism against inflammation of the GI system was demonstrated in an animal study for expe¬rimentally-induced colitis [36]. In an animal model for Crohn's disease, a beneficial, slowing effect of endo¬cannabinoids on intestinal motility has been de¬monstrated [33, 34]. This effect was apparently media¬ted by CB receptors in the gut (and not via the brain). Therefore cannabinoid-based treatment is promising when psychological approaches are not likely to be helpful.
Gastroesophageal reflux disease (GORD). This di-sorder results from a weak lower oesophagal sphincter muscle causing gastric content to flow upward, hence symptoms including heartburn and acid regurgitation appear [41, 56]. The influence of psychological stress, anxiety and depression on this condition has been shown [56-58]. Cannabinoid-based therapies may be developed, acting through cannabinoid receptors in the brain or through peripheral neural control. Indeed, cannabinoid CB1 receptor agonists have been shown to relax the oesophageal sphincter in dogs and ferrets; this effects was mediated by cannabinoid receptors on the vagus nerve at peripheral as well as central sites [22, 26, 27].
Secretory diarrhea. Fluid-induced increase in stool volume, that is, secretory diarrhea, is caused by ab-normal and/or absorption of water and electrolytes as well as dysregulated intestinal motility [59, 60]. Psy-chological stress may precipitate secretory diarrhea. This occurs probably when stress induces the activati¬on of receptors for corticotrophin releasing hormone (CRH1) [60]. Several studies have demonstrated the role of the ECBR system in this process. Thus, stimula¬tion of the ECBR system reduced intestinal fluid ac-cumulation; conversely, the blocking CB1 receptors with the antagonist rimonabant increased fluid accumu¬lation [27]. These observations suggest that the endo¬cannabinoids exert a tonic regulation of intestinal sec¬retory activity which can be up-or down-regulated according to the (psycho)physiological environment. Further, since cannabinoid CB1 receptor activation resulted in decreased fluid accumulation in the small intestine of the rat, cannabinoid-based treatment may be beneficial for diarrhea [61].
Gastric ulcer. The formation of gastric ulcers is known to be stimulated by psychological stress. The ability of cannabinoids to reduce gastric secretions and ulcer formation has been observed many years ago. Interestingly, cannabinoids reduced ulcers which had been caused by stress [62]. This effect may have been achieved by direct activation of cannabinoid receptors in the stomach or by reducing the stress reponse [30] in the central nervous system [63], or by both mecha¬nisms.
Emesis. Antiemetic effects of (endo)cannabinoids have been extensively demonstrated as described above and several '9-THC (dronabinol) or THC-like cannabinoid drugs (the synthetic nabilone) are selectively available for oral clinical use [27, 41, 64, 65]. The antiemetic
effects are mediated by CB1 and CB2 receptors located on gastric vagal nerves or via lower brain structures of the dorsal vagal complex [27, 66]. Taken together, it is widely agreed that CB-based drugs, especially those which do not have central side effects, should be deve¬loped as antiemetic drugs for cancer and AIDS patients who receive chemotherapeutic treatment. Cannabinoids may be especially effective in combating anticipatory nausea and vomiting [67]. Since the area postrema has receptors located outside the brain, CB1 receptor-specific cannabinoids which are not active within the CNS, should be particularly suitable [68, 69].
Neonatal milk intake
Although perhaps one of the major physiological sys-tems (see also Table 1), the ECBR system does not seem critical for survival. Thus for example, the majo¬rity of mice which genetically lack CB1 and/or CB2 receptors, survive into adulthood, albeit with reduced body weights [70-72]. Similarly, very long term treat¬ment (4 months) with the CB1 receptor antagonist ri¬monabant did not cause mortality or (overt) detrimental effects, except for a robust reduction in body weight [73]. In contrast, we have shown that a single injection with rimonabant administered to newborn mice within 24 h of birth, interferes with milk ingestion; this in turn resulted in growth failure and death in many cases. Further investigation into the sequelae of neonatal rimonabant-treatment suggested that CB1 receptor activation in neonates is required for oral-motor deve¬lopment required for sucking [74]. Since the behavioral and physiological deficiencies of CB1 receptor-blocked mouse pups resemble infants suffering from "non-organic failure-to-thrive" (NOFTT), we have suggested that CB1 receptor-blocked neonates may be used as a model for NOFTT and form the basis for the develop¬ment of cannabinoid-based treatments.
Conclusions and future directions
Three major conclusions emanate from the material reviewed here: (i) the ECBR system is a of major me-diating system between the brain, the alimentary sys-tem and the adipose tissue, (ii) it is speculated that the role of the ECBR system in adult regulation of digesti¬on and ingestion may be a remnant of their critical role for the initiation of feeding and survival in the new-born, and (iii) the pervasive influence of the ECBR system in alimentary control, make it a highly suitable target for therapeutic developments aimed at allevia¬ting pathophysiological conditions such as inflammato¬ry bowel disease (IBD), irritable bowel syndrome (IBS), gastric ulcers, nausea, anorexia and obesity.
The CB1 receptor, rather than the CB2 receptor, seems to be the major mediator of ECBR control of the gas-trointestinal tract and food intake, and should therefore be the main target of therapeutic cannabinoid-based drugs. However CB1 receptor agonists often have undesirable psychoactive effects such as confusion and anxiety. We have recently demonstrated that several (+)cannabidiol derivates [such as (+)cannabidiol-demethyl heptyl and (+)carboxy-cannabidiol-demethyl heptyl], displayed CB1-receptor mediated inhibition of intestinal motility in the absence of psychoactive ef¬fects [68, 69]. Further, upregulating the ECBR system by the inhibition of enzymatic breakdown or reuptake inhibition, is expected to yield more selective therapeu¬tic effects, since the manipulation of ECBR function would be restricted to the anatomical sites which are activated at that moment. Preventing endocannabinoid degradation with oleamide, a fatty acid amide which is considered by most [75-78] not to bind CB1 receptors, resulted in psychoactive effects similar to those of anandamide itself [75]. On the other hand, URB597, the highly selective inhibitor of the FAAH enzyme responsible for endocannabinoid breakdown, is thought to have anxiolytic and antidepressant potential without sedative and addictive properties [79]. Thus this or similar FAAH inhibitors may also be useful for the treatment of digestive and ingestive dysfunctions without undesirable psychoactive side effects.
Acknowledgments
This work was supported in part by a grant from San-ofi-Aventis (France) and by intramural support from the College of Judea and Samaria.
References
1. Jones MP, Dilley JB, Drossman D, Crowell MD. Brain-gut connections in functional GI disorders: anatomic and physiologic relationships. Neuro-gastroenterol Motil. 2006; 18:91-103.
2. Konturek SJ, Konturek JW, Pawlik T, Brzo-zowski T. Brain-gut axis and its role in the con-trol of food intake. J Physiol Pharmacol. 2004;55:137-54.
3. Ringel Y. New directions in brain imaging re-search in functional gastrointestinal disorders. Dig Dis. 2006;24:278-85.
4. Fride E. Endocannabinoids in the central nervous system: from neuronal networks to behavior. Curr Drug Targets CNS Neurol Disord. 2005;4:633-42.
5. Strader AD, Woods SC. Gastrointestinal hor-mones and food intake. Gastroenterology. 2005; 128: 175-91.
6. Zhang DM, Bula W, Stellar E. Brain chole-cystokinin as a satiety peptide. Physiol Behav. 1986;36:1 183-6.
7. Shumyatsky GP, Tsvetkov E, Malleret G, Vron-skaya S, Hatton M, Hampton L, Battey JF, Dulac
C, Kandel ER, Bolshakov VY. Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically re-lated to learned fear. Cell. 2002; 111:905-18.
8. Lago F, Gonzalez-Juanatey JR, Casanueva FF, Gomez-Reino J, Dieguez C, Gualillo O. Ghrelin, the same peptide for different functions: player or bystander? Vitam Horm. 2005;71 :405-32.
9. Volkow ND, Wang GJ, Maynard L, Jayne M, Fowler JS, Zhu W, Logan J, Gatley SJ, Ding YS, Wong C, Pappas N. Brain dopamine is associated with eating behaviors in humans. Int J Eat Dis¬ord. 2003;33:136-42.
10. Fride E, Bregman T, Kirkham TC. Endocannabi-noids and food intake: newborn suckling and ap-petite regulation in adulthood. Exp Biol Med (Maywood). 2005;230:225-34.
11. Mechoulam R, Hanus L, Fride E. Towards can-nabinoid drugs--revisited. Prog Med Chem. 1998;35:199-243.
12. Matias I, Gonthier MP, Orlando P, Martiadis V, De Petrocellis L, Cervino C, Petrosino S, Hoareau L, Festy F, Pasquali R, Roche R, Maj M, Pagotto U, Monteleone P, Di Marzo V. Regula¬tion, function, and dysregulation of endocannabi¬noids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab. 2006;91:3171-80.
13. Spoto B, Fezza F, Parlongo G, Battista N, Sgro E, Gasperi V, Zoccali C, Maccarrone M. Human adipose tissue binds and metabolizes the endo-cannabinoids anandamide and 2-arachidonoylglycerol. Biochimie. 2006;88: 1889-97.
14. Howlett AC, Breivogel CS, Childers SR, Dead-wyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of pro-gress. Neuropharmacology. 2004;47 Suppl 1:345-58.
15. Kirkham TC, Williams CM, Fezza F, Di Marzo V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol. 2002; 136:550-7.
16. Fride E, Suris R, Weidenfeld J, Mechoulam R. Differential response to acute and repeated stress in cannabinoid CB 1 receptor knockout newborn and adult mice. Behav Pharmacol. 2005; 16:431 - 40.
17. Patel S, Cravatt BF, Hillard CJ. Synergistic inter-actions between cannabinoids and environmental stress in the activation of the central amygdala. Neuropsychopharmacology. 2005;30:497-507.
18. Hill MN, Gorzalka BB. Increased sensitivity to restraint stress and novelty-induced emotionality following long-term, high dose cannabinoid ex-posure. Psychoneuroendocrinology. 2006;3 1:526-36.
19. Tucci SA, Rogers EK, Korbonits M, Kirkham TC. The cannabinoid CB 1 receptor antagonist SR141 716 blocks the orexigenic effects of intra-hypothalamic ghrelin. Br J Pharmacol. 2004; 143 :520-3.
20. Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G. Leptin-regulated endocannabi-noids are involved in maintaining food intake. Nature. 2001 ;410:822-5.
21. Hornby PJ, Prouty SM. Involvement of cannabi-noid receptors in gut motility and visceral percep¬tion. Br J Pharmacol. 2004;141 :1335-45.
22. Partosoedarso ER, Abrahams TP, Scullion RT, Moerschbaecher JM, Hornby PJ. Cannabinoid1 receptor in the dorsal vagal complex modulates lower oesophageal sphincter relaxation in ferrets. J Physiol. 2003;550:149-58.
23. Van Sickle MD, Oland LD, Mackie K, Davison JS, Sharkey KA. Delta9-tetrahydrocannabinol se-lectively acts on CB 1 receptors in specific re-gions of dorsal vagal complex to inhibit emesis in ferrets. Am J Physiol Gastrointest Liver Physiol. 2003;285:G566-76.
24. Krowicki ZK, Moerschbaecher JM, Winsauer PJ, Digavalli SV, Hornby PJ. Delta9-tetrahydrocannabinol inhibits gastric motility in the rat through cannabinoid CB 1 receptors. Euro¬pean journal of pharmacology. 1 999;371 :187-96.
25. Prestifilippo JP, Fernandez-Solari J, de la Cal C, Iribarne M, Suburo AM, Rettori V, McCann SM, Elverdin JC. Inhibition of salivary secretion by activation of cannabinoid receptors. Exp Biol Med (Maywood). 2006;231:1421-9.
26. Lehmann A, Blackshaw LA, Branden L, Carlsson A, Jensen J, Nygren E, Smid SD. Cannabinoid receptor agonism inhibits transient lower eso¬phageal sphincter relaxations and reflux in dogs. Gastroenterology. 2002; 123:1129-34.
27. Coutts AA, Izzo AA. The gastrointestinal phar-macology of cannabinoids: an update. Curr Opin Pharmacol. 2004;4:572-9.
28. Pertwee RG. Cannabinoids and the gastrointesti-nal tract. Gut. 2001 ;48:859-67.
29. Casu MA, Porcella A, Ruiu S, Saba P, Marchese G, Carai MA, Reali R, Gessa GL, Pani L. Differ-ential distribution of functional cannabinoid CB1 receptors in the mouse gastroenteric tract. Euro-pean journal of pharmacology. 2003;459:97-1 05.
30. Adami M, Frati P, Bertini S, Kulkarni-Narla A, Brown DR, de Caro G, Coruzzi G, Soldani G. Gastric antisecretory role and immunohisto-chemical localization of cannabinoid receptors in the rat stomach. Br J Pharmacol. 2002; 135:1598-606.
31. Coutts AA, Irving AJ, Mackie K, Pertwee RG, Anavi-Goffer S. Localisation of cannabinoid CB(1) receptor immunoreactivity in the guinea pig and rat myenteric plexus. J Comp Neurol. 2002;448:410-22.
32. Landi M, Croci T, Rinaldi-Carmona M, Maffrand JP, Le Fur G, Manara L. Modulation of gastric emptying and gastrointestinal transit in rats through intestinal cannabinoid CB(1) receptors. European journal of pharmacology. 2002;450:77-83.
33. Izzo AA, Fezza F, Capasso R, Bisogno T, Pinto
L, Iuvone T, Esposito G, Mascolo N, Di Marzo V, Capasso F. Cannabinoid CB1-receptor medi-ated regulation of gastrointestinal motility in mice in a model of intestinal inflammation. Br J Pharmacol. 2001; 134:563-70.
34. Izzo AA, Pinto L, Borrelli F, Capasso R, Mascolo N, Capasso F. Central and peripheral cannabinoid modulation of gastrointestinal transit in physio¬logical states or during the diarrhoea induced by croton oil. Br J Pharmacol. 2000;129:1627-32.
35. Manara L, Croci T, Guagnini F, Rinaldi-Carmona
M, Maffrand JP, Le Fur G, Mukenge S, Ferla G. Functional assessment of neuronal cannabinoid receptors in the muscular layers of human ileum and colon. Dig Liver Dis. 2002;34:262-9.
36. Massa F, Marsicano G, Hermann H, Cannich A, Monory K, Cravatt BF, Ferri GL, Sibaev A, Storr M, Lutz B. The endogenous cannabinoid system protects against colonic inflammation. J Clin In-vest. 2004;1 13:1202-9.
37. Hanus L, Abu-Lafi S, Fride E, Breuer A, Vogel Z, Shalev DE, Kustanovich I, Mechoulam R. 2-arachidonyl glyceryl ether, an endogenous ago¬nist of the cannabinoid CB 1 receptor. Proc Natl Acad Sci U S A. 2001;98:3662-5.
38. Izzo AA. Cannabinoids and intestinal motility: welcome to CB2 receptors. Br J Pharmacol. 2004; 142: 1201-2.
39. Mathison R, Ho W, Pittman QJ, Davison JS, Sharkey KA. Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats. Br J Pharma-col. 2004;142:1247-54.
40. Pinto L, Izzo AA, Cascio MG, Bisogno T, Hospodar-Scott K, Brown DR, Mascolo N, Di Marzo V, Capasso F. Endocannabinoids as physiological regulators of colonic propulsion in mice. Gastroenterology. 2002; 123:227-34.
41. Di Carlo G, Izzo AA. Cannabinoids for gastroin-testinal diseases: potential therapeutic applica-tions. Expert Opin Investig Drugs. 2003;12:39-49.
42. Pinto L, Capasso R, Di Carlo G, Izzo AA. Endo-cannabinoids and the gut. Prostaglandins Leukot Essent Fatty Acids. 2002;66:333-41.
43. Fride E. Anandamides: tolerance and cross-tolerance to delta 9-tetrahydrocannabinol. Brain Res. 1995;697:83-90.
44. Mechoulam R, Fride E. Physiology. A hunger for cannabinoids. Nature. 2001 ;410:763, 5.
45. Maccarrone M, Di Rienzo M, Finazzi-Agro A, Rossi A. Leptin activates the anandamide hy-drolase promoter in human T lymphocytes through STAT3. The Journal of biological chem-istry. 2003;278:133 18-24.
46. Bensaid M, Gary-Bobo M, Esclangon A, Maf-frand JP, Le Fur G, Oury-Donat F, Soubrie P. The cannabinoid CB 1 receptor antagonist
SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cul-tured adipocyte cells. Mol Pharmacol. 2003;63:908-14.
47. Bluher M, Engeli S, Kloting N, Berndt J, Fasshauer M, Batkai S, Pacher P, Schon MR, Jordan J, Stumvoll M. Dysregulation of the pe-ripheral and adipose tissue endocannabinoid sys¬tem in human abdominal obesity. Diabetes. 2006;55:3053-60.
48. Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thone-Reineke C, Ortmann S, Tomassoni F, Cervino C, Nisoli E, Linthorst AC, Pasquali R, Lutz B, Stalla GK, Pagotto U. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogene¬sis. J Clin Invest. 2003;112:423-31.
49. Roche R, Hoareau L, Bes-Houtmann S, Gonthier MP, Laborde C, Baron JF, Haffaf Y, Cesari M, Festy F. Presence of the cannabinoid receptors, CB1 and CB2, in human omental and subcutane-ous adipocytes. Histochem Cell Biol. 2006; 126:177-87.
50. Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Batkai S, Harvey-White J, Mackie K, Offertaler L, Wang L, Kunos G. Endocannabi-noid activation at hepatic CB 1 receptors stimu-lates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115:1298-305.
51. Pagotto U, Vicennati V, Pasquali R. The endo-cannabinoid system in the physiopathology of metabolic disorders. Horm Res. 2007;67 Suppl 1:186-90.
52. Wierzbicki AS. Rimonabant: endocannabinoid inhibition for the metabolic syndrome. Int J Clin Pract. 2006;60: 1697-706.
53. Fride E, Mechoulam R. Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. European journal of pharma¬cology. 1993;231 :313-4.
54. Pertwee RG, Fernando SR, Nash JE, Coutts AA. Further evidence for the presence of cannabinoid CB1 receptors in guinea-pig small intestine. Br J Pharmacol. 1996;1 18:2199-205.
55. Hanus L, Breuer A, Tchilibon S, Shiloah S, Goldenberg D, Horowitz M, Pertwee RG, Ross RA, Mechoulam R, Fride E. HU-308: a specific agonist for CB(2), a peripheral cannabinoid re-ceptor. Proc Natl Acad Sci U S A. 1999;96:14228-33.
56. Fass R, Ofman JJ. Gastroesophageal reflux dis-ease--should we adopt a new conceptual frame-work? Am J Gastroenterol. 2002;97: 1901-9.
57. Wright CE, Ebrecht M, Mitchell R, Anggiansah A, Weinman J. The effect of psychological stress on symptom severity and perception in patients with gastro-oesophageal reflux. J Psychosom Res. 2005;59:41 5-24.
58. Richter JE, Bradley LC. Psychophysiological interactions in esophageal diseases. Semin Gas-trointest Dis. 1996;7:169-84.
59. Sanger GJ, Yoshida M, Yahyah M, Kitazumi K. Increased defecation during stress or after 5-hydroxytryptophan: selective inhibition by the 5-HT(4) receptor antagonist, SB-207266. Br J Pharmacol. 2000; 130:706-12.
60. Saunders PR, Maillot C, Million M, Tache Y. Peripheral corticotropin-releasing factor induces diarrhea in rats: role of CRF1 receptor in fecal watery excretion. European journal of pharma-cology. 2002;43 5:231-5.
61. Tyler K, Hillard CJ, Greenwood-Van Meerveld B. Inhibition of small intestinal secretion by can-nabinoids is CB1 receptor-mediated in rats. European journal of pharmacology. 2000;409:207-1 1.
62. Germano MP, D'Angelo V, Mondello MR, Per-golizzi S, Capasso F, Capasso R, Izzo AA, Mas-colo N, De Pasquale R. Cannabinoid CB 1-mediated inhibition of stress-induced gastric ul¬cers in rats. Naunyn Schmiedebergs Arch Phar¬macol. 2001 ;363 :241-4.
63. Patel S, Roelke CT, Rademacher DJ, Cullinan WE, Hillard CJ. Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis. Endocri¬nology. 2004;145:5431-8.
64. Darmani NA. Methods evaluating cannabinoid and endocannabinoid effects on gastrointestinal functions. Methods Mol Med. 2006; 123:169-89.
65. Parker LA, Kwiatkowska M, Burton P, Mechou-lam R. Effect of cannabinoids on lithium-induced vomiting in the Suncus murinus (house musk shrew). Psychopharmacology (Berl). 2004;171:156-61.
66. Van Sickle MD, Duncan M, Kingsley PJ, Moui-hate A, Urbani P, Mackie K, Stella N, Makriyan-nis A, Piomelli D, Davison JS, Marnett LJ, Di Marzo V, Pittman QJ, Patel KD, Sharkey KA. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005;3 10:329-32.
67. Parker LA, Kemp SW. Tetrahydrocannabinol (THC) interferes with conditioned retching in Suncus murinus: an animal model of anticipatory nausea and vomiting (ANV). Neuroreport. 2001; 12:749-51.
68. Fride E, Feigin C, Ponde DE, Breuer A, Hanus L, Arshavsky N, Mechoulam R. (+)-Cannabidiol analogues which bind cannabinoid receptors but exert peripheral activity only. European journal of pharmacology. 2004;506: 179-88.
69. Fride E, Ponde D, Breuer A, Hanus L. Peripheral, but not central effects of cannabidiol derivatives: Mediation by CB(1) and unidentified receptors. Neuropharmacology. 2005;48:1 117-29.
70. Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F, Bohme GA, Imperato A, Pedrazzini T, Roques BP, Vassart G, Fratta W, Parmentier
M. Unresponsiveness to cannabinoids and re-duced addictive effects of opiates in CB1 receptor knockout mice. Science. 1999;283:401-4.
71. Zimmer A, Zimmer AM, Hohmann AG, Herken-ham M, Bonner TI. Increased mortality, hypoac-tivity, and hypoalgesia in cannabinoid CB 1 re-ceptor knockout mice. Proc Natl Acad Sci U S A. 1999;96:5780-5.
72. Paria BC, Song H, Wang X, Schmid PC, Krebs-bach RJ, Schmid HH, Bonner TI, Zimmer A, Dey SK. Dysregulated cannabinoid signaling disrupts uterine receptivity for embryo implantation. The Journal of biological chemistry. 2001 ;276:20523-8.
73. Gobshtis N, Ben-Shabat S, Fride E. Antidepres-sant-induced undesirable weight gain: prevention with rimonabant without interference with behav¬ioral effectiveness. European journal of pharma¬cology. 2007;554:1 55-63.
74. Fride E, Peretz-Ezra D, Arshavsky N, H D, Weller A. The CB 1 receptor and "non-organic failure-to thrive" in infants: the first animal (mouse) model. 33rd Annual Meeting of the So¬ciety for Neuroscience Washington DC, USA. 2005.
75. Mechoulam R, Fride E, Hanus L, Sheskin T, Bisogno T, Di Marzo V, Bayewitch M, Vogel Z. Anandamide may mediate sleep induction. Na-ture. 1997;389:25-6.
76. Sheskin T, Hanus L, Slager J, Vogel Z, Mechou-lam R. Structural requirements for binding of an-andamide-type compounds to the brain cannabi-noid receptor. J Med Chem. 1997;40:659-67.
77. Fowler CJ. Oleamide: a member of the endocan-nabinoid family? Br J Pharmacol. 2004;141 :195-6.
78. Leggett JD, Aspley S, Beckett SR, D'Antona AM, Kendall DA, Kendall DA. Oleamide is a selective endogenous agonist of rat and human CB 1 can-nabinoid receptors. Br J Pharmacol. 2004;141 :253-62.
79. Piomelli D, Tarzia G, Duranti A, Tontini A, Mor M, Compton TR, Dasse O, Monaghan EP, Parrott JA, Putman D. Pharmacological profile of the se-lective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev. 2006;12:21-38.
80. Parker LA, Mechoulam R, Schlievert C, Abbott L, Fudge ML, Burton P. Effects of cannabinoids on lithium-induced conditioned rejection reac¬tions in a rat model of nausea. Psychopharmacol¬ogy (Berl). 2003;166:156-62.
Source: The endogenous cannabinoid system: a new player in the brain-gut-adipose axis
