Post-inflammatory Hypersensitivity Research Articles

Mo2029 Extracellular Cyclic GMP (cGMP), the Downstream Mediator Released in Response to Linaclotide-Induced Activation of Guanylate Cyclase-C (GC-C), Reduces Excitability of Murine and Human Dorsal Root Ganglion (DRG) Neurons

G A A b st ra ct s that was performed every 4 days to determine the exact timepoint of endoscopic healing in each individual animal. Three days after endoscopic resolution of inflammation, visceral sensitivity was assessed by quantifying visceromotor responses (VMRs) to colorectal distension. A-317491 (10-25 mg/kg) or saline was administered 30 min prior to VMR testing. Compliance was evaluated by applying graded volumes to the colorectally inserted balloon and recording the corresponding colonic pressures. Afterwards remaining signs of inflammation were assessed by endoscopy, macroscopy, histology and myeloperoxidase activity. P2X3R mRNA expression was determined in colon specimens and dorsal root ganglia (DRGs; Th13-L2 and L6-S1) by RT-PCR. Results: Endoscopy demonstrated that colitis was present 3 days after the TNBS enema and had resolved by day 12 (range 10-14); inflammatory markers were normal in control and post-colitis rats at the time of VMR testing. After endoscopic healing of colitis, post-colitis rats displayed significant visceral hypersensitivity compared to controls (table 1). Post-inflammatory hypersensitivity was dose-dependently reduced by A-317491 without affecting VMRs in controls. Colonic compliance was comparable in both groups and remained unaltered by A-317491 (n=5-7). P2X3RmRNAwas similarly expressed in the colon and DRGs of control and post-colitis rats. Conclusion: The selective P2X3R antagonist A-317491 dose-dependently reduced post-inflammatory visceral hypersensitivity, highlighting the modulatory role of P2X3Rs in visceral nociception. Our findings validate this receptor subtype as a potential target in the treatment of abdominal pain syndromes such as irritable bowel syndrome and inflammatory bowel disease. Table 1. Visceromotor responses to colorectal distension in control and post-colitis rats.

Postinflammatory visceral sensitivity and pain mechanisms

The inflammatory reaction is normally tightly regulated, and as soon as the original insult has been cleared, a resolution phase starts that aims at leading the tissues back to a normal physiological state. However, after intestinal inflammation, a number of patients develop postinflammatory hypersensitivity symptoms, which can be defined as an excessive sensitivity to gut nociceptive stimulation. The pain experienced by those patients has been largely studied in the context of postinfectious intestinal diseases. The mechanisms of postinflammatory persistent visceral pain involve peripheral and central neuroplastic changes, low-grade chronic inflammation that sensitizes visceral afferent pathways and sensitization of non-neuronal resident cells of the gut. Several molecular determinants such as neurokinins, serotonin, proteases and voltage-gated ion channels seem to play a significant role in the control of postinflammatory visceral sensation. This review tries to give insights into the mechanisms of persistent visceral pain following the resolution of intestinal inflammation and tries to identify what needs to be done to further advance the field of postinflammatory hypersensitivity clinical management.

T1426 Delayed Post-Inflammatory Hypersensitivity in Sub-Populations of Colonic Afferents

T1426 Delayed Post-Inflammatory Hypersensitivity in Sub-Populations of Colonic Afferents

5-Amino-2-hydroxybenzoic Acid 4-(5-Thioxo-5H-[1,2]dithiol-3yl)-phenyl Ester (ATB-429), a Hydrogen Sulfide-Releasing Derivative of Mesalamine, Exerts Antinociceptive Effects in a Model of Postinflammatory Hypersensitivity

H(2)S functions as a neuromodulator and exerts anti-inflammatory activities. Recent data indicate that irritable bowel syndrome (IBS) is linked to inflammation of the gastrointestinal tract. In this study, we have investigated the role of a novel H(2)S-releasing derivative of mesalamine (5-amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3yl)-phenyl ester, ATB-429) in modulating nociception to colorectal distension (CRD), a model that mimics some features of IBS, in healthy and postcolitic rats. Four graded (0.4-1.6 ml of water) CRDs were produced in conscious rats, and colorectal sensitivity and pain were assessed by measuring the abdominal withdrawal response and spinal c-Fos expression. In healthy rats, ATB-429 dose dependently (25, 50, or 100 mg/kg) attenuated CRD-induced hypersensitivity and significantly inhibited CRD-induced overexpression of spinal c-FOS mRNA, whereas mesalamine had no effect. ATB-429-induced antinociception was reversed by glibenclamide, a ATP-sensitive K(+) (K(ATP)) channel inhibitor. The antinociceptive effect of ATB-429 was maintained in a rodent model of postinflammatory hypersensitivity (4 weeks after colitis induction). At a dose of 100 mg/kg, ATB-429 reversed the allodynic response caused by CRD in postcolitic rats. Colonic cyclooxygenase-2 and interkeukin-1beta mRNA and spinal c-FOS mRNA expression were significantly down-regulated by ATB-429, but not by mesalamine. ATB-429, but not mesalamine, increased blood concentrations of H(2)S in both healthy and postcolitic rats. Taken together, these data suggest that ATB-429 inhibits hypersensitivity induced by CRD in both healthy and postcolitic, allodynic rats by a K(ATP) channel-mediated mechanism. This study provides evidence that H(2)S-releasing drugs might have beneficial effects in the treatment of painful intestinal disorders.