Neonatal maternal separation enhances central sensitivity to noxious colorectal distention in rat

Psychological stress experienced in early life plays an important role in the development of visceral hyperalgesia in irritable bowel syndrome (IBS). Neonatal maternal separation has been shown to trigger a long-term alternation in stress-induced responses to visceral nociceptive stimuli in rats. The aim of the present study was to show a direct evidence of stress-induced alteration in central neuronal responses to colorectal distention (CRD) in rats by a quantitative study of c-fos expression in relevant brain structures. Male Wistar rat pups were subjected to 180-min daily neonatal maternal separation (NMS) for 13 consecutive days (from PND 2 to PND 14). The expression of c-fos was examined by using immunohistochemistry. Increased c-fos expression was observed, for the first time, in the cingulate cortex (3-fold) in NMS rats in comparison with the control group at basal condition. At noxious CRD (80 mm Hg), c-fos expression was induced in the supraspinal centers and in both the superficial (laminae I-II) and the deeper laminae (laminae V-VI and X) of the spinal cord in rats. Significantly more Fos-IR nuclei were found in the laminae I and II, and laminae V-VI of the lumbarsacral spinal cord, the paraventricular thalamic nucleus, the cingulate cortex, the amygdaloid central nucleus in NMS rats, but not in the solitary tract, the central medial thalamic nucleus, the ventromedial hypothalamic nucleus, and the periaquaductal gray. The present results indicate that NMS has sensitized the cingulate cortex and upregulated the activity of the ascending pathway at spinal level as well as the thalamo-cortico-amydala pathway to CRD. The upregulation and sensitization of these pathways may be responsible for the development of visceral hypersensitivity in IBS.