Julie Gardener
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Cannabinoids and intestinal motility: welcome to CB2 receptors
Angelo A Izzo1*
1Department of Experimental Pharmacology, University of Naples Federico II, via D Montesano 49, 80131 Naples, Italy
*Author for correspondence: Email: aaizzo@unina.it
Received April 16, 2004; Accepted May 21, 2004.
This article has been cited by other articles in PMC.
Abstract
Δ9-Tetrahydrocannabinol (the active ingredient of marijuana), as well as endogenous and synthetic cannabinoids, exert many biological functions by activating two types of cannabinoid receptors, CB1 receptors (expressed by central and peripheral neurons) and CB2 receptors (that occur mainly in immune cells). Convincing evidence has accumulated in recent years that cannabinoids inhibit gastric and intestinal motility through activation of enteric CB1 receptors. However, a report in this issue of British Journal of Pharmacology has highlighted the possibility that CB2 receptors in the rat intestine could contribute to reducing the increase of intestinal motility induced by an endotoxic inflammation. By minimizing the adverse psychotropic effects associated with brain cannabinoid receptors, the CB2 receptor represents a new molecular target for the treatment of motility disorders associated with intestinal inflammation.
Botanical preparations of Cannabis sativa (Indian hemp) have been widely used in the past to treat a variety of disorders including those affecting the digestive tract. In 1964, Δ9-tetrahydrocannabinol (Δ9-THC) was isolated, and was later shown to be responsible for many of the pharmacological actions of Cannabis preparations. The understanding of the mechanism by which marijuana exerts its pharmacological actions has seen considerable progress following the discovery in the early 1990s of specific membrane, G-protein-coupled receptors for Δ9-THC, namely CB1 receptors, expressed by central and peripheral nerves (including the enteric nervous system), and CB2 receptors, which occur mainly in immune cells. The discovery of these receptors has led to the demonstration that there are endogenous agonists for these receptors. The best known are anandamide, 2-arachidonylglycerol (2-AG) (nonselective cannabinoid receptor agonists), noladin ether (CB1 receptor agonist) and virodhamine (CB1 receptor antagonist/CB2 receptor agonist). When released, anandamide and 2-AG are removed from extracellular compartments by a carrier-mediated reuptake process, and once within the cell, both endocannabinoids are hydrolyzed by the enzyme fatty acid amide hydrolase (also named anandamide amidohydrolase). In addition to the two cannabinoid receptors, anandamide and 2-AG (both detected in the gut) can also activate vanilloid receptors, the molecular target for the pungent plant compound capsaicin (for a review, see De Petrocellis et al., 2004).
Several recent, independent investigations provide compelling evidence that cannabinoids reduce gastrointestinal motility through activation of enteric CB1 receptors. Cannabinoid receptor agonists affect motility of isolated intestinal segments in a manner that resembles the neuromodulatory response to prejunctional μ-opioid receptor or α2-adrenoceptor activation of cholinergic, postganglionic parasympathetic neurones. Thus, a number of cannabinoid receptor agonists (via CB1 activation) have been shown to reduce or inhibit excitatory transmission, neural acetylcholine release and peristalsis efficiency in isolated intestinal segments. A functional evidence for the presence of prejunctional CB1 in the human isolated ileum and colon, through which the cannabinoid receptor agonist WIN55,212-2 inhibited electrically evoked contractile responses, has also been demonstrated. Consistent with these in vitro studies, cannabinoid receptor agonists reduce gastric, small intestinal and colonic motility in rodents in vivo, an effect counteracted by the selective CB1 receptor antagonist SR141716A, but not by the selective CB2 receptor antagonist SR144528. Interestingly, a CB1-mediated reduction of intestinal motility has been observed also in some pathophysiological states in mice, including the experimental ileus induced by intraperitoneal administration of acetic acid and the model of intestinal inflammation induced by oral croton oil (for a review, see Di Carlo & Izzo, 2003).
In this issue of the British Journal of Pharmacology, Mathison et al. (2004) provide pharmacological evidence that the CB1-mediated reduction of gastrointestinal transit was absent in rats treated with an endotoxic inflammatory agent, being replaced by a CB2-mediated inhibition of stimulated transit. It is reported that the selective CB2 receptor agonist JWH-133 was without effect in control animals, but it reduced the increase in gastrointestinal transit induced by intraperitoneal administration of lipopolysaccharide (LPS). The effect of JWH-133 was dose dependent and it was prevented by the selective CB2 receptor antagonist AM-630. Perhaps surprisingly, the selective CB1 receptor agonist ACEA inhibited motility in control rats but it was without effect in mice treated with LPS. The authors hypothesised that the lack of effect of CB1 receptor on LPS-stimulated gastrointestinal transit might reflect an inactivation of this receptor by this inflammatory stimulus. It is very unlikely that CB2 receptors are tonically activated by endogenous cannabinoids in this model of intestinal inflammation, since the CB2 antagonist alone was without effect in the LPS-induced increase in transit. Notably, it has been recently reported that endogenous cannabinoid anandamide exerts a protective role on cholera toxin-induced fluid accumulation via activation of overexpressed CB1 receptors on enteric cholinergic nerves (Izzo et al., 2003).
To examine the role of putative mediators that might be involved in the inhibition of LPS-stimulated increase in gastrointestinal transit by CB2 receptors, the authors evaluated a number of antagonists/inhibitors in the absence and presence of the CB2 receptor agonist JWH-133. Based on these experiments, it was convincingly demonstrated that the CB2 agonist acted via cyclooxygenase metabolites and independently of inducible nitric oxide synthase (NOS) and platelet-activating factor (PAF). Indeed, indomethacin completely abrogated the inhibitory effect of JWH-133, while the PAF receptor antagonist PCA 4248 or the inducible NOS inhibitor SATU did not modify JWH-133-induced motility changes. Preliminary evidence for the possible involvement of interleukin-1β or endothelial NOS was also provided. Based upon these results and the literature, it is hypothesized that cannabinoids act on CB2 receptors expressed by inflammatory/immune and/or epithelial cells to inhibit the release of inflammatory mediators, which are known to stimulate intestinal peristalsis. Consistent with this scenario, Ihenetu and colleagues have recently reported that TNF-α-induced interleukin-8 release was inhibited by cannabinoids through activation of CB2 receptors in human colonic epithelial cells, which are recognised to exert a major influence in the maintenance of intestinal immune homeostasis (Ihenetu et al., 2003).
The potential therapeutic value of such findings seems to be relevant. Activation of CB2 receptors represents a novel mechanism for the re-establishment of normal gastrointestinal transit after an inflammatory stimulus. The strategy to use selective CB2 receptor agonists for the treatment of hypermotility during inflammatory bowel diseases is highly promising because it is likely to be devoid of the well-known Cannabis unwanted effects (e.g. sedation, cognitive dysfunction, ataxia and psychotropic effects), which are due to activation of brain CB1 receptors. Also, it will be interesting to see in future studies whether a CB2 mechanism exists to protect the gut from the fluid hypersecretion and mucosal damage associated to endotoxic inflammation. Clearly, further exploration of the role of CB2 receptors in the gut is likely to produce worthwhile results.
Abbreviations
2-AG 2-arachidonylglycerol
Δ9-THC tetrahydrocannabinol
LPS lipopolysaccharide
NOS nitric oxide synthase
References
DE PETROCELLIS L., CASCIO M.G., DI MARZO V. The endocannabinoid system: a general view and latest additions. Br. J. Pharmacol. 2004;141:765—774. [PMC free article] [PubMed]
DI CARLO G., IZZO A.A. Cannabinoids for gastrointestinal diseases: potential therapeutic applications. Expert Opin. Investig. Drugs. 2003;12:39—49.
IHENETU K., MOLLEMAN A., PARSONS M.E., WHELAN C.J. Inhibition of interleukin-8 release in the human colonic epithelial cell line HT-29 by cannabinoids. Eur. J. Pharmacol. 2003;458:207—215. [PubMed]
IZZO A.A., CAPASSO F., COSTAGLIOLA A., BISOGNO T., MARSICANO G., LIGRESTI A., MATIAS I., CAPASSO R., PINTO L., BORRELLI F., CECIO A., LUTZ B., MASCOLO N., DI MARZO V. An endogenous cannabinoid tone attenuates cholera toxin-induced fluid accumulation in mice. Gastroenterology. 2003;125:765—774. [PubMed]
MATHISON R., HO W., PITTMAN Q.J.M., DAVISON J.S., SHARKEY K.A. Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats. Br J. Pharmacol. 2004;142:1247—1254. [PMC free article] [PubMed]
Source: Cannabinoids and intestinal motility: welcome to CB2 receptors
Angelo A Izzo1*
1Department of Experimental Pharmacology, University of Naples Federico II, via D Montesano 49, 80131 Naples, Italy
*Author for correspondence: Email: aaizzo@unina.it
Received April 16, 2004; Accepted May 21, 2004.
This article has been cited by other articles in PMC.
Abstract
Δ9-Tetrahydrocannabinol (the active ingredient of marijuana), as well as endogenous and synthetic cannabinoids, exert many biological functions by activating two types of cannabinoid receptors, CB1 receptors (expressed by central and peripheral neurons) and CB2 receptors (that occur mainly in immune cells). Convincing evidence has accumulated in recent years that cannabinoids inhibit gastric and intestinal motility through activation of enteric CB1 receptors. However, a report in this issue of British Journal of Pharmacology has highlighted the possibility that CB2 receptors in the rat intestine could contribute to reducing the increase of intestinal motility induced by an endotoxic inflammation. By minimizing the adverse psychotropic effects associated with brain cannabinoid receptors, the CB2 receptor represents a new molecular target for the treatment of motility disorders associated with intestinal inflammation.
Botanical preparations of Cannabis sativa (Indian hemp) have been widely used in the past to treat a variety of disorders including those affecting the digestive tract. In 1964, Δ9-tetrahydrocannabinol (Δ9-THC) was isolated, and was later shown to be responsible for many of the pharmacological actions of Cannabis preparations. The understanding of the mechanism by which marijuana exerts its pharmacological actions has seen considerable progress following the discovery in the early 1990s of specific membrane, G-protein-coupled receptors for Δ9-THC, namely CB1 receptors, expressed by central and peripheral nerves (including the enteric nervous system), and CB2 receptors, which occur mainly in immune cells. The discovery of these receptors has led to the demonstration that there are endogenous agonists for these receptors. The best known are anandamide, 2-arachidonylglycerol (2-AG) (nonselective cannabinoid receptor agonists), noladin ether (CB1 receptor agonist) and virodhamine (CB1 receptor antagonist/CB2 receptor agonist). When released, anandamide and 2-AG are removed from extracellular compartments by a carrier-mediated reuptake process, and once within the cell, both endocannabinoids are hydrolyzed by the enzyme fatty acid amide hydrolase (also named anandamide amidohydrolase). In addition to the two cannabinoid receptors, anandamide and 2-AG (both detected in the gut) can also activate vanilloid receptors, the molecular target for the pungent plant compound capsaicin (for a review, see De Petrocellis et al., 2004).
Several recent, independent investigations provide compelling evidence that cannabinoids reduce gastrointestinal motility through activation of enteric CB1 receptors. Cannabinoid receptor agonists affect motility of isolated intestinal segments in a manner that resembles the neuromodulatory response to prejunctional μ-opioid receptor or α2-adrenoceptor activation of cholinergic, postganglionic parasympathetic neurones. Thus, a number of cannabinoid receptor agonists (via CB1 activation) have been shown to reduce or inhibit excitatory transmission, neural acetylcholine release and peristalsis efficiency in isolated intestinal segments. A functional evidence for the presence of prejunctional CB1 in the human isolated ileum and colon, through which the cannabinoid receptor agonist WIN55,212-2 inhibited electrically evoked contractile responses, has also been demonstrated. Consistent with these in vitro studies, cannabinoid receptor agonists reduce gastric, small intestinal and colonic motility in rodents in vivo, an effect counteracted by the selective CB1 receptor antagonist SR141716A, but not by the selective CB2 receptor antagonist SR144528. Interestingly, a CB1-mediated reduction of intestinal motility has been observed also in some pathophysiological states in mice, including the experimental ileus induced by intraperitoneal administration of acetic acid and the model of intestinal inflammation induced by oral croton oil (for a review, see Di Carlo & Izzo, 2003).
In this issue of the British Journal of Pharmacology, Mathison et al. (2004) provide pharmacological evidence that the CB1-mediated reduction of gastrointestinal transit was absent in rats treated with an endotoxic inflammatory agent, being replaced by a CB2-mediated inhibition of stimulated transit. It is reported that the selective CB2 receptor agonist JWH-133 was without effect in control animals, but it reduced the increase in gastrointestinal transit induced by intraperitoneal administration of lipopolysaccharide (LPS). The effect of JWH-133 was dose dependent and it was prevented by the selective CB2 receptor antagonist AM-630. Perhaps surprisingly, the selective CB1 receptor agonist ACEA inhibited motility in control rats but it was without effect in mice treated with LPS. The authors hypothesised that the lack of effect of CB1 receptor on LPS-stimulated gastrointestinal transit might reflect an inactivation of this receptor by this inflammatory stimulus. It is very unlikely that CB2 receptors are tonically activated by endogenous cannabinoids in this model of intestinal inflammation, since the CB2 antagonist alone was without effect in the LPS-induced increase in transit. Notably, it has been recently reported that endogenous cannabinoid anandamide exerts a protective role on cholera toxin-induced fluid accumulation via activation of overexpressed CB1 receptors on enteric cholinergic nerves (Izzo et al., 2003).
To examine the role of putative mediators that might be involved in the inhibition of LPS-stimulated increase in gastrointestinal transit by CB2 receptors, the authors evaluated a number of antagonists/inhibitors in the absence and presence of the CB2 receptor agonist JWH-133. Based on these experiments, it was convincingly demonstrated that the CB2 agonist acted via cyclooxygenase metabolites and independently of inducible nitric oxide synthase (NOS) and platelet-activating factor (PAF). Indeed, indomethacin completely abrogated the inhibitory effect of JWH-133, while the PAF receptor antagonist PCA 4248 or the inducible NOS inhibitor SATU did not modify JWH-133-induced motility changes. Preliminary evidence for the possible involvement of interleukin-1β or endothelial NOS was also provided. Based upon these results and the literature, it is hypothesized that cannabinoids act on CB2 receptors expressed by inflammatory/immune and/or epithelial cells to inhibit the release of inflammatory mediators, which are known to stimulate intestinal peristalsis. Consistent with this scenario, Ihenetu and colleagues have recently reported that TNF-α-induced interleukin-8 release was inhibited by cannabinoids through activation of CB2 receptors in human colonic epithelial cells, which are recognised to exert a major influence in the maintenance of intestinal immune homeostasis (Ihenetu et al., 2003).
The potential therapeutic value of such findings seems to be relevant. Activation of CB2 receptors represents a novel mechanism for the re-establishment of normal gastrointestinal transit after an inflammatory stimulus. The strategy to use selective CB2 receptor agonists for the treatment of hypermotility during inflammatory bowel diseases is highly promising because it is likely to be devoid of the well-known Cannabis unwanted effects (e.g. sedation, cognitive dysfunction, ataxia and psychotropic effects), which are due to activation of brain CB1 receptors. Also, it will be interesting to see in future studies whether a CB2 mechanism exists to protect the gut from the fluid hypersecretion and mucosal damage associated to endotoxic inflammation. Clearly, further exploration of the role of CB2 receptors in the gut is likely to produce worthwhile results.
Abbreviations
2-AG 2-arachidonylglycerol
Δ9-THC tetrahydrocannabinol
LPS lipopolysaccharide
NOS nitric oxide synthase
References
DE PETROCELLIS L., CASCIO M.G., DI MARZO V. The endocannabinoid system: a general view and latest additions. Br. J. Pharmacol. 2004;141:765—774. [PMC free article] [PubMed]
DI CARLO G., IZZO A.A. Cannabinoids for gastrointestinal diseases: potential therapeutic applications. Expert Opin. Investig. Drugs. 2003;12:39—49.
IHENETU K., MOLLEMAN A., PARSONS M.E., WHELAN C.J. Inhibition of interleukin-8 release in the human colonic epithelial cell line HT-29 by cannabinoids. Eur. J. Pharmacol. 2003;458:207—215. [PubMed]
IZZO A.A., CAPASSO F., COSTAGLIOLA A., BISOGNO T., MARSICANO G., LIGRESTI A., MATIAS I., CAPASSO R., PINTO L., BORRELLI F., CECIO A., LUTZ B., MASCOLO N., DI MARZO V. An endogenous cannabinoid tone attenuates cholera toxin-induced fluid accumulation in mice. Gastroenterology. 2003;125:765—774. [PubMed]
MATHISON R., HO W., PITTMAN Q.J.M., DAVISON J.S., SHARKEY K.A. Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats. Br J. Pharmacol. 2004;142:1247—1254. [PMC free article] [PubMed]
Source: Cannabinoids and intestinal motility: welcome to CB2 receptors
