Peripheral corticotropin releasing hormone mediates post-inflammatory visceral hypersensitivity in rats

Abstract

Aim: To investigate whether peripheral corticotropin releasing hormone (CRH), which is up-regulated in intestinal inflammation, mediates the post-inflammatory visceral hypersensitivity in a rat model of colitis.

Methods: We measured mucosal myeloperoxidase (MPO) activity as a marker of inflammation, plasma CRH level, and abdominal withdrawal reflex (AWR) to colorectal distension as a visceral nociceptive response at 2, 7 and 14 d after the induction of colitis with 4% acetic acid.

Results: Colonic inflammation, quantified by MPO activity, significantly increased on d 2 and subsided thereafter, which indicated a resolution of inflammation within 7 d. On the contrary, plasma CRH level and AWR score were increased on d 2, remained high on d 7, and returned to control level on d 14. Intraperitoneal injection of a CRH antagonist, astressin (30 mug/kg), significantly attenuated the post-inflammatory visceral hypersensitivity on d 7. Furthermore, intraperitoneal administration of CRH (3 and 10 mug/kg) mimicked the post-inflammatory visceral hypersensitivity in naive rats.

Conclusion: These results suggest that increased peripheral CRH mediates the enhanced visceral nociception in rats recovered from experimental colitis.

Figure 1

Colitis-induced changes in colonic mucosal MPO activity (A), plasma level of CRH (B), and visceral nociceptive AWR (C). In panel A and B, the upper and lower whiskers indicate the maximum and minimum values, respectively. Box lines represent the 25th (bottom), 50th (middle) and 75th (top) percentile value; (C) The area under the curve (AUC) calculated from the stimulus-response plot is illustrated as a bar graph on the right side. ^aP < 0.05, ^bP < 0.01 vs control by MWU test after KW test (P < 0.01).

Figure 2

Effect of CRH receptor antagonist astressin (A) and CRH (B) on the colorectal distension-induced AWR behavior. In each panel, the bar graphs on the right side represent the AUC of the stimulus-response plot. Astressin (AST, 30 μg/kg) and CRH (1, 3 and 10 μg/kg) were administered intraperitoneally. The same amount of saline was given as a vehicle (Veh). ^aP < 0.05 vs the paired group in (A) or the Veh group in (B) by MWU test after KW test (P < 0.05).