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• W2065227344 abstract "In a recent TiPS article1xThe endo-cannabinoid system as a target for therapeutic drugs. Piomelli, D. et al. Trends Pharmacol. Sci. 2000; 21: 218–224Abstract | Full Text | Full Text PDF | PubMed | Scopus (356)See all References1, Piomelli et al. discussed recent advances in the biochemistry and pharmacology of the endocannabinoid system in relation to the opportunities that this system offers for the development of novel therapeutic agents. The authors described three physiological processes in which the endocannabinoid system might serve important regulatory functions – nociception, central excitatory neuro-transmission and dopamine-mediated control of movement – and outlined the possible application of cannabinoid agents to pathological conditions associated with such physiological processes. Here, we wish to draw attention to the pharmacological relevance of the presence of cannabinoid receptors located in the gastrointestinal tract. In our opinion, the strategic location of these receptors could provide future pharmacological strategies for the clinical management of gut-motility disorders.The presence of mRNA for cannabinoid CB1, but not CB2, receptors has been demonstrated on myenteric nerves of the guinea-pig small intestine2xEvidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals. Griffin, G. et al. Eur. J. Pharmacol. 1997; 339: 53–61Crossref | PubMed | Scopus (139)See all References2. In this tissue, activation of prejunctional CB1 receptors elicits inhibition of excitatory transmission2xEvidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals. Griffin, G. et al. Eur. J. Pharmacol. 1997; 339: 53–61Crossref | PubMed | Scopus (139)See all References2, which is associated with a decrease in acetylcholine release and a reduction of peristaltic efficiency3xCannabinoid inhibition of guinea-pig intestinal peristalsis via inhibition of excitatory and activation of inhibitory neural pathways. Heinemann, A. et al. Neuropharmacology. 1999; 38: 1289–1297Crossref | PubMed | Scopus (60)See all References3. These effects, which have been confirmed in human intestinal tissues4xIn vitro functional evidence of neuronal cannabinoid CB1 receptors. Croci, T. et al. Br. J. Pharmacol. 1998; 125: 1393–1396Crossref | PubMedSee all References4, resemble the putative actions of mu opioid receptor and α2-adrenoceptor agonists in intestinal tissues.In vivo studies have emphasized the importance of enteric CB1 receptors in the control of intestinal motility. Both central and peripheral CB1 receptors could modulate gastrointestinal motility; however, the inhibitory effect of systemic (intraperitoneally injected) cannabinoid receptor agonists is mediated by peripheral receptors5xCentral and peripheral cannabinoid modulation of gastrointestinal transit in physiological states or during the diarrhoea induced by croton oil. Izzo, A.A. et al. Br. J. Pharmacol. 2000; 129: 1627–1632Crossref | PubMedSee all References5. Interestingly, the potency of cannabinoid receptor agonists is greatly enhanced via a peripheral mechanism in mice with inflammatory diarrhoea compared with controls, thus raising the possibility that enteric CB1 receptors are sensitized or upregulated in pathophysiological states5xCentral and peripheral cannabinoid modulation of gastrointestinal transit in physiological states or during the diarrhoea induced by croton oil. Izzo, A.A. et al. Br. J. Pharmacol. 2000; 129: 1627–1632Crossref | PubMedSee all References5. These findings support previous anecdotal reports that the use of marijuana could ameliorate the symptoms of diarrhoea.There is also evidence that intestinal motility could be physiologically inhibited by endogenous cannabinoids. Indeed, the presence of the endocannabinoid receptor agonist 2-arachidonylglycerol has been demonstrated in the canine gut, whereas the rat small intestine contains significant concentrations of anandamide hydrolase6xDistribution of anandamide amidohydrolase in rat tissues with special reference to small intestine. Katayama, K. et al. Biochim. Biophys. Acta. 1997; 1347: 212–218Crossref | PubMed | Scopus (73)See all References6, the enzyme responsible for the inactivation of the endocannabinoid anandamide. Functional studies indicate that SR141716A, a specific CB1 receptor antagonist, administered alone, can produce motility changes that are opposite in direction to those of cannabinoid receptor agonists5xCentral and peripheral cannabinoid modulation of gastrointestinal transit in physiological states or during the diarrhoea induced by croton oil. Izzo, A.A. et al. Br. J. Pharmacol. 2000; 129: 1627–1632Crossref | PubMedSee all References5. These effects, however, cannot be attributed unequivocally to displacement of endocannabinoids because SR141716A behaves as an inverse agonist at CB1 receptors.In conclusion, there is a body of evidence in favour of a CB1-receptor-mediated modulation of intestinal motility. The major role of these receptors seems to be that of a ‘braking’ mechanism, which operates when intestinal functions are over-stimulated by excitatory neurotransmitters or possibly by inflammatory mediators. It now appears evident that selective, non-psychotropic compounds that act at CB1 receptors could represent novel drugs to either decrease gut activity (e.g. CB1 receptor agonists for the treatment of gut spasms or inflammatory diarrhoea) or increase motility (e.g. CB1 receptor antagonists for the treatment of ileus). It should be noted that the cannabinoid receptor agonist WIN552122 prevents pentagastrin-induced gastric acid secretion7xInhibitory effect of the cannabinoid receptor agonist WIN 55,212-2 on pentagastrin-induced gastric acid secretion in the anaesthetized rat. Coruzzi, G. et al. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1999; 3: 60See all References7 and stress-induced gastric ulceration in the rat (A.A. Izzo, unpublished) via activation of CB1 receptors. Future research into this area is also likely to unveil possible gastroprotective agents. Nevertheless, ‘the journey of a thousand miles begins with a single step’." @default.
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• W2065227344 title "Forgotten target for marijuana: the endocannabinoid system in the gut" @default.
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