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SUSTAINED HYPEREXCITABILITY OF NOCICEPTIVE DRG NEURONS FOLLOWING INFLAMMATION IN A CITROBACTER RODENTIUM MODEL OF POST- INFECTIOUS IRRITABLE BOWEL SYNDROME (IBS)
CO Ibeakanma, F Bautista-Cruz, M Richards, D Hurlbut, N Martin, S Vanner
GIDRU, Queen’s University, Kingston, Ontario
Many patients develop chronic IBS symptoms, including pain, following a bout of acute infectious gastroenteritis but it is unclear whether the expression of pain is due to central and/or peripheral neural mechanisms. To determine if peripheral mechanisms play a role, we developed a mouse model using Citrobacter rodentium (mimics human E. Coli self-limiting colitis) which enabled us to make whole cell recordings from labeled nociceptive dorsal root ganglia (DRG) neurons innervating the colon, at the height of infection (day 10) and when the infection had resolved (day 30). To measure changes in excitability, recordings were obtained in current clamp mode to determine rheobase, number of action potentials at two times rheobase, resting membrane potential, and input resistance from infected mice and compared to controls gavaged with distilled water. At day 10, the rheobase (mean = 37.8 ± 2.74 pA vs. 63.6 ± 11.7 pA; p-value = 0.0230), number of action potentials at 2x rheobase (mean = 4.3 ± 0.4 vs. 2.8 ± 0.51; p-value = 0.0209) and the resting membrane potential (mean = –42.4 ± 0.43 mV vs. –45.9 ± 0.72 mV; p-value = 0.0001) differed significantly between neurons isolated from infected and control mice respectively. MPO measurements and pathological assessment by an observer blinded to the treatments confirmed the presence of a significant difference in colonic Inflammation (mean composite score = 3.8 ± 0.33 vs. 0.33 ± 0.17; p-value = 0.0001) and the mean crypt height (mean composite score = 198.6 ± 9.1 µm vs. 110.6 ± 8.79 µm; p-value = 0.0001) between the Citrobacter and control tissues respectively. At day 30, MPO measurements returned to control values, stool cultures were negative for Citrobacter infection and inflammation scores matched controls in most tissues. In those tissues where inflammation was resolved, the mean number of action potentials at 2x rheobase still showed a 3 fold increase (mean = 3.5 ± 1.1 vs. 1.1 ± 0.14 pA; p-value = 0.0354). This persistent excitability after the bacterial infection has resolved suggests that peripheral mechanisms (i.e. changes in DRG nociceptive neurons) could play a role in the persisting pain symptoms observed in patients suffering from post-infectious IBS. Suppression of K+ IA currents could account for these changes.