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

Abstract

Irritable bowel syndrome is characterized by altered sensory qualities, namely discomfort/pain and colorectal hypersensitivity. In mice, we examined the role of P2X(3) receptors in colon mechanosensitivity and intracolonic zymosan-produced hypersensitivity, a model of persistent colon hypersensitivity without colon inflammation. The 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 P2X(3) receptor contributions to colon mechanosensation and hypersensitivity, electrophysiologic experiments were performed using an in vitro colon-pelvic nerve preparation. Visceromotor responses to distension were significantly reduced in P2X(3)(+/-) and P2X(3)(-/-) mice relative to wild-type mice. Colon hypersensitivity produced by zymosan was virtually absent in P2X(3)(-/-) relative to wild-type or P2X(3)(+/-) mice. Intralumenal release of the endogenous P2X receptor ligand adenosine triphosphate did not differ between wild-type and P2X(3)(-/-) mice or change after intracolonic zymosan treatment. Responses of muscular and muscular-mucosal pelvic nerve afferents to mechanical stretch did not differ between P2X(3)(-/-) 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 P2X(3)(-/-) mice. These results suggest differential roles for peripheral and central P2X(3) receptors in colon mechanosensory transduction and hypersensitivity.