Abstract
ObjectivesExperiments using P2X3 knock-out mice or more general P2X receptor antagonists suggest that P2X3 receptors contribute to visceral hypersensitivity. We aimed to investigate the effect of the selective P2X3 antagonist A-317491 on visceral sensitivity under physiological conditions, during acute colitis and in the post-inflammatory phase of colitis.MethodsTrinitrobenzene sulphonic-acid colitis was monitored by colonoscopy: on day 3 to confirm the presence of colitis and then every 4 days, starting from day 10, to monitor convalescence and determine the exact timepoint of endoscopic healing in each rat. Visceral sensitivity was assessed by quantifying visceromotor responses to colorectal distension in controls, rats with acute colitis and post-colitis rats. A-317491 was administered 30 min prior to visceral sensitivity testing. Expression of P2X3 receptors (RT-PCR and immunohistochemistry) and the intracellular signalling molecules cdk5, csk and CASK (RT-PCR) were quantified in colonic tissue and dorsal root ganglia. ATP release in response to colorectal distension was measured by luminiscence.ResultsRats with acute TNBS-colitis displayed significant visceral hypersensitivity that was dose-dependently, but not fully, reversed by A-317491. Hypersenstivity was accompanied by an increased colonic release of ATP. Post-colitis rats also displayed visceral hypersensitivity that was dose-dependently reduced and fully normalized by A-317491 without increased release of ATP. A-317491 did not modify visceral sensitivity in controls. P2X3 mRNA and protein expression in the colon and dorsal root ganglia were similar in control, acute colitis and post-colitis groups, while colonic mRNA expression of cdk5, csk and CASK was increased in the post-colitis group only.ConclusionsThese findings indicate that P2X3 receptors are not involved in sensory signaling under physiological conditions whereas they modulate visceral hypersensitivity during acute TNBS-colitis and even more so in the post-inflammatory phase, albeit via different mechanisms of sensitization, validating P2X3 receptors as potential new targets in the treatment of abdominal pain syndromes.
Highlights
Abdominal pain is a common symptom in many gastrointestinal disorders, among which the irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD)
P2X3 mRNA and protein expression in the colon and dorsal root ganglia were similar in control, acute colitis and post-colitis groups, while colonic mRNA expression of cdk5, csk and CASK was increased in the post-colitis group only. These findings indicate that P2X3 receptors are not involved in sensory signaling under physiological conditions whereas they modulate visceral hypersensitivity during acute TNBS-colitis and even more so in the post-inflammatory phase, albeit via different mechanisms of sensitization, validating P2X3 receptors as potential new targets in the treatment of abdominal pain syndromes
The functional evidence implicating the P2X3 and P2X2/3 receptor subtypes in gut sensory signaling has come mainly from experiments using either knock-out mice or nonselective P2X antagonists such as TNP-adenosine 5’-triphospate (ATP), that acts on P2X3 and P2X2/3 receptors and displays nanomolar affinity for P2X1, or PPADS that blocks all types of P2X receptors [13,14,15,16,17,18,19,20]
Summary
Abdominal pain is a common symptom in many gastrointestinal disorders, among which the irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). P2X3 receptors are the predominant purinergic receptor subtypes present in the dorsal root ganglia (DRGs) [9,10] They are found mainly on small and medium-sized neurons, which are considered to be nociceptive C-fibers, and on a subpopulation of Aδ-fibers [9,11,12]. The potential of specific P2X3 unit targeted therapy has been hardly explored in animal models of gut hypersensitivity [20]. Such antagonists have already progressed to phase II clinical trials for hypersensitivity-associated disorders such as interstitial cystitis, osteoarthritis and idiopathic chronic cough (http://clinicaltrials.gov) [11]. Despite its relevance from a clinical point-of-view, little in vivo evidence is available on the role of P2X3 receptor modulation of visceral sensory function in models of longer-lasting visceral pain
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