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Comparative Study
. 2008 Dec;135(6):2075-83.
doi: 10.1053/j.gastro.2008.08.051. Epub 2008 Sep 3.

A rat model of chronic postinflammatory visceral pain induced by deoxycholic acid

Richard J Traub  1 , Bin Tang, Yaping Ji, Sangeeta Pandya, Harris Yfantis, Ying Sun
Affiliations
Comparative Study

A rat model of chronic postinflammatory visceral pain induced by deoxycholic acid

Richard J Traub et al. Gastroenterology. 2008 Dec.

Abstract

Background & aims: Chronic visceral hyperalgesia is considered an important pathophysiologic symptom in irritable bowel syndrome (IBS); previous gastrointestinal inflammation is a potent etiologic factor for developing IBS. Although there are several animal models of adult visceral hypersensitivity after neonatal perturbation or acute colonic irritation/inflammation, current models of postinflammatory chronic visceral hyperalgesia are unsatisfactory. The aim of this study was to establish a model of chronic visceral hyperalgesia after colonic inflammation in the rat.

Methods: Deoxycholic acid (DCA) was instilled into the rat colon daily for 3 days and animals were tested for up to 4 weeks.

Results: DCA induced mild, transient colonic inflammation within 3 days that resolved within 3 weeks. An exaggerated visceromotor response, referred pain to mechanical stimulation, increased spinal Fos expression, and colonic afferent and dorsal horn neuron activity were apparent by 1 week and persisted for at least 4 weeks, indicating chronic dorsal horn hyperexcitability and visceral hyperalgesia. There was no spontaneous pain, based on open field behavior. There was a significant increase in opioid-receptor activity.

Conclusions: DCA induces mild, transient colitis, resulting in persistent visceral hyperalgesia and referred pain in rats, modeling some aspects of postinflammatory IBS.

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Figures

Figure 1
Figure 1
DCA induces mild, transient colonic inflammation. A: Plasma extravasation 3 and 7 days following intracolonic injection of DCA or saline, no CRD; * p<0.05 vs. saline, n= 4–8 rats/ group. B: Plasma extravasation 1 and 4 weeks following DCA or saline plus CRD; * p<0.05, n= 12/group. C: MPO activity measured weekly following DCA or saline injection; *p<0.05 vs. saline, n=4/group. D: The number of polymorphonuclear neutrophils per field following DCA or saline, n=8/group. E: The number of Mast cells per section of colon following DCA or saline; *p<0.05 vs. saline, n= 4–8/group. F: The number of fecal pellets following DCA or saline injection; *p<0.05 vs. saline, n=11/group.
Figure 2
Figure 2
DCA induces visceral hypersensitivity that persists beyond resolution of the inflammation. A: the magnitude of the vmr to 60 mmHg CRD before (baseline) and 1 week following saline or DCA injection, * p<0.001 vs. baseline, # p<0.01 vs. 1 week saline, n=12–16/group. B: Time course of visceral hypersensitivity to graded intensities of CRD in DCA-treated rats. * p<0.05 vs. all time points, n=10 rats.
Figure 3
Figure 3
DCA increases activity of colonic afferents and dorsal horn neurons. A: Effects of DCA on LS colonic afferents 1 and 4 weeks following injection, n=17–18 cells/group. * p<0.05, ** p<0.01, *** p<0.001 vs. saline; ++ p<0.01, +++ p<0.001 vs. 1 wk DCA. B: Effects of DCA on the response to CRD of TL and LS dorsal horn neurons 1 and 4 weeks following injection. * p<0.05 vs. saline, n= 8–14 cells/group.
Figure 4
Figure 4
DCA increases Fos expression in the LS and TL spinal segments. Effect of DCA and CRD on Fos expression in the LS (top) and TL (bottom) spinal segments 1 and 4 weeks after injection. S0/D0: saline or DCA, no CRD; S60/D60: saline or DCA + 60 mmHg CRD. * p<0.05 vs. saline (s0). + p<0.05 vs. DCA + CRD at 1 week (D60), n=4–8/group.
Figure 5
Figure 5
DCA induces referred pain. The % withdrawals to von Frey filaments applied to the caudal back following DCA, n=8 rats.
Figure 6
Figure 6
DCA increases opioid analgesia. A, Left: The magnitude of the visceromotor response (bar graph) before (b) and 1 week following injection of saline or DCA; * p<0.05. Right: Dose-response curves for morphine in saline and DCA-treated rats as the % maximum possible effect (%MPE); * p<0.05 vs. saline, n=8/group. B: Naloxone facilitated the vmr 1 week following DCA, but not saline, administration; * paired t-test, p<0.05 vs. baseline, n=4–6/group.
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