Purinergic contribution to small intestinal afferent hypersensitivity in a murine model of postinfectious bowel disease.
Increased sensitivity of the afferent innervation of the gastrointestinal tract reportedly underlies symptoms of discomfort and pain in functional bowel disorders. The present investigation aimed to examine whether the purinergic P2X(2) and P2X(3) receptor subunits contribute to the mechanosensitivity of small intestinal afferents in normal mice and in a murine model of postinfectious gut dysfunction. Mesenteric afferent nerve activity was recorded in a mouse jejunum preparation maintained in vitro. As has been shown previously, ramp distension of the jejunal segment evoked biphasic afferent discharge, reflecting activation of low and high threshold fibres. The average pressure-afferent response curve in mice deficient in both P2X(2) and P2X(3) subunits (n = 14) was not significantly different from that of the wild-type control preparations (n = 13). Application of pyridoxal 5-phosphate 6-azophenyl-2 ,4-disulphonic acid (PPADS) (30 micromol L(-1)), a P2X and P2Y antagonist, or 2,4,6-trinitrophenol-adenosine 5'-triphosphate (10 micromol L(-1)), an antagonist selective for homomeric P2X(3) and heteromeric P2X(2/3) receptors, had no effect on the averaged pressure-afferent response curve in wild-type animals. In Trichinella spiralis-infected mice, the magnitude of mesenteric afferent responses to jejunal distension was greater at day 21 and day 56 postinfection compared with the sham control preparations demonstrating the development of afferent hypersensitivity. PPADS had no significant effect upon mechanically evoked afferent discharge rates in sham treated preparations (n = 5), but significantly inhibited afferent sensitivity to jejunal distension in preparations from mice at day 21 (n = 6) and day 56 (n = 7) postinfection. These results suggest that purinergic mechanisms play no role in mechanosensory transduction in the normal small intestine but contribute significantly to postinfectious mechano-hypersensitivity.
Rong
W
W
Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Keating
C
C
Sun
B
B
Dong
L
L
Grundy
D
D
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D005456:Fluorescent Dyes; D006967:Hypersensitivity / Q000503:physiopathology*; D007421:Intestine, Small / Q000503:physiopathology*; D043183:Irritable Bowel Syndrome / Q000209:etiology* / Q000503:physiopathology*; D008643:Mesentery / Q000294:innervation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D010812:Physical Stimulation; D058913:Purinergic Agonists; D058914:Purinergic Antagonists; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D011983:Receptors, Purinergic / Q000235:genetics*; D018048:Receptors, Purinergic P2 / Q000235:genetics; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D015398:Signal Transduction / Q000187:drug effects; D017160:Trichinella spiralis; D014235:Trichinellosis / Q000150:complications*
D005456:Fluorescent Dyes; C546402:P2rx2 protein, mouse; C546409:P2rx3 protein, mouse; D058913:Purinergic Agonists; D058914:Purinergic Antagonists; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D011983:Receptors, Purinergic; D018048:Receptors, Purinergic P2; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate; C045674:2',3'-O-(2,4,6-trinitro-cyclohexadienylidine)adenosine 5'-triphosphate; D000255:Adenosine Triphosphate