A study of mechanisms underlying inflammation-induced abnormal nociceptive signaling from the colon in models of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD)
Ibeakanma, Charles Onyinye
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Abdominal pain is a common symptom of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Although the extent differs, visceral inflammation is thought to play a significant role in nociception in these disorders. This thesis describes studies examining mechanisms of inflammation-induced changes in nociceptive signaling from the colon using human colonic biopsy and animal models of the conditions. Citrobacter rodentium infection in mice produced profound colitis at day 10 post-infection which resolved by day 30. Perforated current clamp recordings showed that inflammation induced hyperexcitability of colonic DRG neurons that persisted at day 30 post-infection. Similarly, multi-unit afferent nerve recordings revealed enhanced firing of colonic afferents following colon distension at this time. In voltage clamp studies, suppression of IA K+ currents in post-infected C. rodentium neurons was observed. Combining water-avoidance stress (WAS) and C. rodentium infection exaggerated these effects. Interactions between proteases and stress mediators underlie these actions. In vivo studies revealed WAS combined with C. rodentium post-infection induced visceral hyperalgesia and allodynia. A separate series of studies examined the possible role of cysteine proteases in post-infectious IBS. The cysteine protease cathepsin-s (Cat-S) induced neuronal excitability and, provoked visceral hypersensitivity in mice. Human IBS supernatants increased neuronal excitability, but this was reversed in neurons pre-treated with the cysteine protease inhibitor E-64. Together these data suggest that Cat-S is a secreted neuromodulator in human IBS supernatants and could be important in nociceptive signaling in IBS. In studies examining whether similar mechanisms operate in a traditional inflammatory condition, IBD, human ulcerative colitis (UC) supernatants showed elevated TNF-α levels. Exogenous TNF-α and UC-supernatants increased colonic nociceptor excitability, which was attenuated in neurons from TNFR knock-out animals. TNF-α and UC-supernatants both increased TTX-R Nav1.8 and suppressed IA and IK K+ currents. Together these results suggest that inflammation significantly increases and sustains peripheral nociceptive signaling in IBD and IBS. These effects involve changes in the properties of nociceptive DRG neurons through actions of specific secreted factors which modulate specific voltage-gated ion channels. Chronic stress exaggerates these changes through synergistic actions of stress hormones and local mediators, suggesting an interplay between central and peripheral mechanisms.