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Background: The autonomic nervous system plays an important role in regulating colorectal motility. Surgical and obstetrical trauma has long been cited as a cause for abnormal colorectal motility in humans. Using a rat model, we have recently shown that parasympathetic nerve damage immediately impairs colonic transit and that over time colonic transit is restored, consistent with what is seen clinically. The physiologic mechanisms by which denervation causes abnormal motility and by which this adaptation process takes place remains unclear. Since the peristaltic reflex is mediated by extrinsic and intrinsic neural reflexes via mucosal serotonin (5-HT) and via 5-HT4 receptors within the lamina propria of the rat colon, we hypothesized that restoration of normal colonic transit, following parasympathetic damage is mediated by up-regulation of 5-HT4 receptors within the intrinsic nervous system. Methods: 30 SD rats underwent placement of a tunneled catheter into the proximal colon. 22 underwent parasympathetic denervation (bilateral vagotomy and transection of pelvic nerves) while the others received a sham operation. To measure colonic transit, 51Cr was injected into the proximal colon at post op days 1, 3, and 7 and the geometric center (GC) of distribution of Cr was calculated. 10 SD rats were divided into 2 groups, sham operation and parasympathetic denervation. At post op day 3, mucosa/submucosal layers of the proximal, middle and distal colon were harvested. 5-HT4 receptor expression was evaluated by Western blot and real time PCR. Results: At post op day 1, colonic parasympathetic denervation caused a significant decrease in GC (4.4, p<0.01, n=6), compared to sham operation (6.3, n=8). Between post op days 3 and 7, there was a significant trend of increasing GC [5.2 at day 3, (n=8) and 6.0, p<0.05 (n=8)] in the denervation group. 5-HT4 receptor protein expression was significantly increased in the distal colon in the denervation group (n=5, P<0.01), compared to sham operation group (n=5). A trend toward significance was seen in 5-HT4 receptor mRNA expression in the denervation group (n=5, P=0.06), compared to sham operation group (n=5). Conclusions: Mucosal colonic 5-HT4 receptors are upregulated following parasympathetic denervation of the distal colon in rats. Upregulation of 5-HT4 receptors of intrinsic origin may be a contributing factor in the mechanism involved in restoring normal colorectal motility after parasympathetic denervation.