ABSTRACT
Title
Control of enteric neuromuscular functions by adenosine receptors under normal conditions and in the presence of bowel inflammation
Authors
L. Antonioli1, M. Fornai1, R. Colucci1, O. Awwad1, M. Tuccori1, A. Bin2, R.M. Gaion2, I. Castagliuolo3, M.C. Giron2,C. Blandizzi1
1Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Pisa, Italy, 2Department of Pharmacology and Anesthesiology, University of Padova, Padova, Italy, 3Department of Histology, Microbiology and Medical Biotechnologies, University of Padova, Italy.
1Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Pisa, Italy, 2Department of Pharmacology and Anesthesiology, University of Padova, Padova, Italy, 3Department of Histology, Microbiology and Medical Biotechnologies, University of Padova, Italy.
Abstract
Inflammatory bowel disorders are associated with complex structural and/or functional alterations of the enteric nervous system (ENS) and smooth muscle cells, which can contribute to severe disturbances of gut motility. Changes in the neurophysiology of enteric neural circuits can account for motor dysfunctions occurring in the inflamed bowel, and there is evidence that such abnormalities depend on mutual interactions between the ENS and cells of the enteric immune/inflammatory system. In this regard, increasing attention is being paid to the adenosine system, which represents a crucial point of interaction between neuromuscular and immune enteric components, suggesting an active role of adenosine in the regulation of gastrointestinal functions, both under physiological conditions and in the presence of gut motor disorders associated with bowel inflammation.
In recent years,our group has focused its attention on the expression of adenosine receptors in the enteric neuromuscular compartment and their role in the control of colonic motility in the presence of experimental colitis. Efforts are being dedicated also to characterize the enteric nerve pathways subjected to modulation by these receptors.We have obtained evidence that, under normal conditions, all adenosine receptor subtypes are expressed in the colonic neuromuscular layer, and that they are involved in the tonic inhibitory control of excitatory cholinergic motor activity, acting both at neuronal level (A1, A2A and A3 receptors) and through a direct modulation of smooth muscle contraction (A2B receptors). In the presence of bowel inflammation, the adenosine receptor pathways are subjected to several dynamic changes in their expression and/or function, with a marked increase in A2A and A3 receptor expression. However, this receptor rearrangement correlates only in part with the patterns of evoked contractile activity recorded in functional experiments. In this setting, the enhancing effects resulting from the blockade of A1, A2B or A3 receptors, on the electrically induced cholinergic contractions, were no longer evident in the presence of colitis, while the potentiating effect obtained by A2A receptor blockade was more pronounced as compared to normal conditions. In experiments where the levels of endogenous extracellular adenosine were decreased, the pharmacological stimulation of all adenosine receptor subtypes was able to inhibit the electrically induced contractions, and the efficacy of the inhibitory effects mediated by A2A or A3 receptors was higher than that observed in normal colonic preparations. This discrepancy, between the effects recorded under normal conditions and in the presence of colitis, suggests that, during bowel inflammation, all adenosine receptors are present in the colonic neuromuscular compartment, and are available for pharmacological recruitment, even if only A2A receptors appear to be preferentially and tonically recruited by endogenous adenosine. In this regard, it is being increasingly appreciated that adenosine receptor activation is subjected to fine regulation by synthetic or catabolic enzymes and transporters, which channel the production of endogenous adenosine into discrete microenvironments, thus leading to compartmental recruitments of specific receptor subtypes
Overall, our findings add new plugs for understanding the contribution of adenosine receptor pathways in the control of gut motility, demonstrating a molecular and functional rearrangement of adenosine receptors in the presence of colitis. These observations, together with increasing knowledge relating adenosine receptor subtypes with the modulation of immune/inflammatory processes, might represent a promising basis for the development of novel pharmacological tools potentially useful for the therapeutic management of enteric dysmotility associated with bowel inflammation.
In recent years,our group has focused its attention on the expression of adenosine receptors in the enteric neuromuscular compartment and their role in the control of colonic motility in the presence of experimental colitis. Efforts are being dedicated also to characterize the enteric nerve pathways subjected to modulation by these receptors.We have obtained evidence that, under normal conditions, all adenosine receptor subtypes are expressed in the colonic neuromuscular layer, and that they are involved in the tonic inhibitory control of excitatory cholinergic motor activity, acting both at neuronal level (A1, A2A and A3 receptors) and through a direct modulation of smooth muscle contraction (A2B receptors). In the presence of bowel inflammation, the adenosine receptor pathways are subjected to several dynamic changes in their expression and/or function, with a marked increase in A2A and A3 receptor expression. However, this receptor rearrangement correlates only in part with the patterns of evoked contractile activity recorded in functional experiments. In this setting, the enhancing effects resulting from the blockade of A1, A2B or A3 receptors, on the electrically induced cholinergic contractions, were no longer evident in the presence of colitis, while the potentiating effect obtained by A2A receptor blockade was more pronounced as compared to normal conditions. In experiments where the levels of endogenous extracellular adenosine were decreased, the pharmacological stimulation of all adenosine receptor subtypes was able to inhibit the electrically induced contractions, and the efficacy of the inhibitory effects mediated by A2A or A3 receptors was higher than that observed in normal colonic preparations. This discrepancy, between the effects recorded under normal conditions and in the presence of colitis, suggests that, during bowel inflammation, all adenosine receptors are present in the colonic neuromuscular compartment, and are available for pharmacological recruitment, even if only A2A receptors appear to be preferentially and tonically recruited by endogenous adenosine. In this regard, it is being increasingly appreciated that adenosine receptor activation is subjected to fine regulation by synthetic or catabolic enzymes and transporters, which channel the production of endogenous adenosine into discrete microenvironments, thus leading to compartmental recruitments of specific receptor subtypes
Overall, our findings add new plugs for understanding the contribution of adenosine receptor pathways in the control of gut motility, demonstrating a molecular and functional rearrangement of adenosine receptors in the presence of colitis. These observations, together with increasing knowledge relating adenosine receptor subtypes with the modulation of immune/inflammatory processes, might represent a promising basis for the development of novel pharmacological tools potentially useful for the therapeutic management of enteric dysmotility associated with bowel inflammation.