Peripheral and Central P2X3 Receptor Contributions to Colon Mechanosensitivity and Hypersensitivity in the Mouse

Background & AimsIrritable bowel syndrome is characterized by altered sensory qualities, namely discomfort/pain and colorectal hypersensitivity. In mice, we examined the role of P2X3 receptors in colon mechanosensitivity and intracolonic zymosan-produced hypersensitivity, a model of persistent colon hypersensitivity without colon inflammation.MethodsThe visceromotor response to colon distension (15–60 mm Hg) was determined before and after intracolonic saline or zymosan (30 mg/mL, 0.1 mL, daily for 3 days) treatment. Colon pathology and intracolonic adenosine triphosphate release was assessed in parallel experiments. To examine P2X3 receptor contributions to colon mechanosensation and hypersensitivity, electrophysiologic experiments were performed using an in vitro colon-pelvic nerve preparation.ResultsVisceromotor responses to distension were significantly reduced in P2X3+/− and P2X3−/− mice relative to wild-type mice. Colon hypersensitivity produced by zymosan was virtually absent in P2X3−/− relative to wild-type or P2X3+/− mice. Intralumenal release of the endogenous P2X receptor ligand adenosine triphosphate did not differ between wild-type and P2X3−/− mice or change after intracolonic zymosan treatment. Responses of muscular and muscular-mucosal pelvic nerve afferents to mechanical stretch did not differ between P2X3−/− and wild-type mice. Both muscular and muscular-mucosal afferents in wild-type mice sensitized to application of an inflammatory soup, whereas only muscular-mucosal afferents did so in P2X3−/− mice.ConclusionsThese results suggest differential roles for peripheral and central P2X3 receptors in colon mechanosensory transduction and hypersensitivity.