Abstract
Repeated water avoidance stress (WAS) induces sustained visceral hyperalgesia (VH) in rats measured as enhanced visceromotor response to colorectal distension (CRD). This model incorporates two characteristic features of human irritable bowel syndrome (IBS), VH and a prominent role of stress in the onset and exacerbation of IBS symptoms. Little is known regarding central mechanisms underlying the stress-induced VH. Here, we applied an autoradiographic perfusion method to map regional and network-level neural correlates of VH. Adult male rats were exposed to WAS or sham treatment for 1 hour/day for 10 days. The visceromotor response was measured before and after the treatment. Cerebral blood flow (CBF) mapping was performed by intravenous injection of radiotracer ([14C]-iodoantipyrine) while the rat was receiving a 60-mmHg CRD or no distension. Regional CBF-related tissue radioactivity was quantified in autoradiographic images of brain slices and analyzed in 3-dimensionally reconstructed brains with statistical parametric mapping. Compared to sham rats, stressed rats showed VH in association with greater CRD-evoked activation in the insular cortex, amygdala, and hypothalamus, but reduced activation in the prelimbic area (PrL) of prefrontal cortex. We constrained results of seed correlation analysis by known structural connectivity of the PrL to generate structurally linked functional connectivity (SLFC) of the PrL. Dramatic differences in the SLFC of PrL were noted between stressed and sham rats under distension. In particular, sham rats showed negative correlation between the PrL and amygdala, which was absent in stressed rats. The altered pattern of functional brain activation is in general agreement with that observed in IBS patients in human brain imaging studies, providing further support for the face and construct validity of the WAS model for IBS. The absence of prefrontal cortex-amygdala anticorrelation in stressed rats is consistent with the notion that impaired corticolimbic modulation acts as a central mechanism underlying stress-induced VH.
Highlights
Considerable evidence links stress with the onset and symptom exacerbation in irritable bowel syndrome (IBS) [1,2,3]
We have shown that patterns of brain activation in response to acute colorectal distension (CRD) and in expectation of CRD in the rat are in general agreement with that reported in the human brain imaging literature [10,12,13]
Results of the SPM seed correlation analysis were only analyzed for those regions structurally connected with the prelimbic area (PrL). This is equivalent to taking an intersection of the structural and functional connectivity network of the PrL, resulting in an structurally linked functional connectivity (SLFC) network (Fig. 2)
Summary
Considerable evidence links stress with the onset and symptom exacerbation in irritable bowel syndrome (IBS) [1,2,3]. Visceromotor responses measured as abdominal electromyographic signals evoked by colorectal distension (CRD), are most commonly used to assess stress-induced visceral hyperalgesia, modeling a cardinal symptom of IBS. Given the multidimensional nature of pain, the visceromotor response in rodents likely reflects only a portion of the complex human visceral pain experience. Comparing alterations in CRD-evoked brain responses in stress-induced visceral hyperalgesic rodents and that reported in IBS patients by human brain imaging studies can provide important validation for the stress-based animal models for human IBS. A better understanding of such stress-induced alterations in brain nociceptive responses is critical to delineating the underlying mechanisms
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