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GENETICALLY MODIFIED ANIMALS AND MODEL ORGANISMS

Enhanced pelvic responses to stressors in female CRF-overexpressing mice

¹CURE: Digestive Diseases Research Center and Center for Neurovisceral Sciences and Women's Health, Department of Medicine, Division of Digestive Diseases, University of California, and VA Greater Los Angeles Healthcare System, Los Angeles, California; ²Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; ³The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, California; and ⁴Department of Veterinary Clinical Sciences, The Ohio State University, Columbus, Ohio

Submitted 1 September 2006 ; accepted in final form 30 November 2006

Acute stress affects gut functions through the activation of corticotropin-releasing factor (CRF) receptors. The impact of acute stress on pelvic viscera in the context of chronic stress is not well characterized. We investigated the colonic, urinary, and locomotor responses monitored as fecal pellet output (FPO), urine voiding, and ambulatory activity, respectively, in female and male CRF-overexpressing (CRF-OE) mice, a chronic stress model, and their wild-type littermates (WTL). Female CRF-OE mice, compared with WTL, had enhanced FPO to 2-min handling (150%) and 60-min novel environment (155%) but displayed a similar response to a 60-min partial restraint stress. Female CRF-OE mice, compared with WTL, also had a significantly increased number of urine spots (7.3 ± 1.4 vs. 1.3 ± 0.8 spots/h) and lower locomotor activity (246.8 ± 47.8 vs. 388.2 ± 31.9 entries/h) to a novel environment. Male CRF-OE mice and WTL both responded to a novel environment but failed to show differences between them in colonic and locomotor responses. Male WTL, compared with female WTL, had higher FPO (113%). In female CRF-OE mice, the CRF₁/CRF₂ receptor antagonist astressin B and the selective CRF₂ receptor agonist mouse urocortin 2 (injected peripherally) prevented the enhanced defecation without affecting urine or locomotor responses to novel environment. RT-PCR showed that CRF₁ and CRF₂ receptors are expressed in the mouse colonic tissues. The data show that chronic stress, due to continuous central CRF overdrive, renders female CRF-OE mice to have enhanced pelvic and altered behavioral responses to superimposed mild stressors and that CRF₁-initiated colonic response is counteracted by selective activation of CRF₂ receptor.

chronic stress; colon; urine; locomotor activity; astressin B; mouse urocortin 2

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