Submitted on August 27, 2006
Accepted on October 30, 2006
Effects of neonatal maternal separation on neurochemical and sensory response to colonic distension in a rat model of irritable bowel syndrome
Tian-Hua Ren1, Justin Wu2, David Yew3, Eric Tat Chi Ziea2, Lixing Lao4, Wai-Keung Leung2, Brian Berman4, Pin-Jin Hu5, and Joseph JY Sung2*
1 Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China; Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong
2 Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong
3 Anatomy, The Chinese University of Hong Kong, Hong Kong
4 Center for Integrative Medicine, University of Maryland, Maryland, United States
5 First Affiliated Hospital of Sun Yat-sen University of Medical Sciences, Guangzhou, China
* To whom correspondence should be addressed. E-mail: joesung{at}cuhk.edu.hk.
Background and Aims: Early life stress has been implicated as a risk factor for irritable bowel syndrome (IBS). We studied the effect of neonatal maternal separation on the viscero-motor response and expression of c-fos, 5-HT and its receptors/transporters along the brain-gut axis in an animal model of IBS.
Methods: Male neonatal Sprague-Dawley rats were randomly assigned to 3-hour daily maternal separation (MS) or non-handling (NH) on postnatal day 2-21. Colorectal balloon distention (CRD) was performed for assessment of abdominal withdrawal reflex (AWR) as a surrogate marker of visceral pain. Tissues from dorsal raphe nucleus in mid-brain, lumbar-sacral cord and distal colon were harvested for semi-quantitative analysis of c-fos and 5-HT. The expression of 5-HT expression, 5-HT3 receptors and 5-HT transporter (5HTT) were analyzed by RT-PCR.
Results: Pain threshold was significantly lower in MS rats and their AWR responses to CRD were significantly higher with distension pressures of 40, 60 and 80 mmHg. In MS rats, the number of c-fos-like immunoreactive nuclei at dorsal horn of lumbar-sacral spinal cord increased significantly after CRD. 5-HT content in the spinal cord of MS rats was significant higher. In the colon, both 5-HT positive cell number and 5-HT content were comparable between MS and NH groups before CRD. Post-CRD only MS rats had significant increase in 5-HT content. Protein and mRNA expression levels of 5-HT3 receptors and 5-HTT were similar in MS and NH rats.
Conclusions: Neonatal maternal separation stress predisposes rats to exaggerated neurochemical responses and visceral hyperalgesia in colon mimicking IBS.
