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Purinergic contribution to small intestinal afferent hypersensitivity in a murine model of postinfectious bowel
1Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Abstract:
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.
Insights
Purinergic receptors P2X(2) and P2X(3) do not affect normal gut mechanosensitivity. However, these receptors significantly contribute to hypersensitivity in post-infectious gut dysfunction, suggesting a therapeutic target for visceral pain.
Area of Science:
- Gastroenterology
- Neuroscience
- Pharmacology
Background:
- Functional bowel disorders are linked to heightened sensitivity of gastrointestinal afferent nerves.
- Purinergic receptors, specifically P2X(2) and P2X(3) subunits, are implicated in sensory pathways.
Purpose of the Study:
- To investigate the role of P2X(2) and P2X(3) receptor subunits in small intestinal mechanosensitivity.
- To determine if these receptors contribute to hypersensitivity in a mouse model of post-infectious gut dysfunction.
Main Methods:
- Recorded mesenteric afferent nerve activity in an in vitro mouse jejunum preparation.
- Utilized gene-deficient mice lacking P2X(2) and P2X(3) subunits.
- Administered P2X/P2Y antagonist (PPADS) and selective P2X(3) antagonist.
- Compared responses in normal mice and mice infected with Trichinella spiralis.
Main Results:
- Absence of P2X(2) and P2X(3) subunits did not alter normal jejunal mechanosensitivity.
- Pharmacological antagonism of P2X receptors had no effect on mechanosensitivity in wild-type mice.
- Post-infectious gut dysfunction model showed increased afferent responses to distension.
- PPADS significantly inhibited this hypersensitivity in infected mice.
Conclusions:
- Purinergic mechanisms are not involved in normal small intestinal mechanosensory transduction.
- P2X(2) and P2X(3) receptors play a significant role in the development of post-infectious gut mechano-hypersensitivity.
- Targeting these purinergic receptors may offer a therapeutic strategy for visceral pain in functional bowel disorders.
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