Regulation of enteric functions by adenosine: pathophysiological and pharmacological implications

The wide distribution of ATP and adenosine receptors as well as enzymes for purine metabolism in different gut regions suggests a complex role for these mediators in the regulation of gastrointestinal functions. Studies in rodents have shown a significant involvement of adenosine in the control of intestinal secretion, motility and sensation, via activation of A1, A2A, A2B or A3 purinergic receptors, as well as the participation of ATP in the regulation of enteric functions, through the recruitment of P2X and P2Y receptors. Increasing interest is being focused on the involvement of ATP and adenosine in the pathophysiology of intestinal disorders, with particular regard for inflammatory bowel diseases (IBDs), intestinal ischemia, post-operative ileus and related dysfunctions, such as gut dysmotility, diarrhoea and abdominal discomfort/pain. Current knowledge suggests that adenosine contributes to the modulation of enteric immune and inflammatory responses, leading to anti-inflammatory actions. There is evidence supporting a role of adenosine in the alterations of enteric motor and secretory activity associated with bowel inflammation. In particular, several studies have highlighted the importance of adenosine in diarrhoea, since this nucleoside participates actively in the cross-talk between immune and epithelial cells in the presence of diarrhoeogenic stimuli. In addition, adenosine exerts complex regulatory actions on pain transmission at peripheral and spinal sites. The present review illustrates current information on the role played by adenosine in the regulation of enteric functions, under normal or pathological conditions, and discusses pharmacological interventions on adenosine pathways as novel therapeutic options for the management of gut disorders and related abdominal symptoms.