Abstract

Background and aims: Cyclooxygenase 2 (COX-2) and prostaglandins (PGs) participate in the pathogenesis of inflammatory postoperative ileus. We sought to determine whether the emerging neuronal modulator COX-2 plays a significant role in primary afferent activation during postoperative ileus using spinal Fos expression as a marker.

Methods: Rats, and COX-2^+/+ and COX-2^−/− mice underwent simple intestinal manipulation. The effect of intestinal manipulation on Fos immunoreactivity (IR) in the L₅-S₁ spinal cord, in situ circumference, and postoperative leucocytic infiltrate of the intestinal muscularis was measured. Postoperative PGE₂ production was measured in peritoneal lavage fluid. The dependence of these parameters on COX-2 was studied in pharmacological (DFU, Merck- Frosst, selective COX-2 inhibitor) and genetic (COX-2^−/− mice) models.

Results: Postoperative Fos IR increased 3.7-fold in rats and 2.2-fold in mice. Both muscularis leucocytic infiltrate and the circumference of the muscularis increased significantly in rats and COX-2^+/+ mice postoperatively, indicating dilating ileus. Surgical manipulation markedly increased PGE₂ levels in the peritoneal cavity. DFU pretreatment and the genetic absence of COX-2^−/− prevented dilating ileus, and leucocytic infiltrate was diminished by 40% with DFU and by 54% in COX-2^−/− mice. DFU reversed postsurgical intra- abdominal PGE₂ levels to normal. Fos IR after intestinal manipulation was attenuated by approximately 50% in DFU treated rats and in COX-2^−/− mice.

Conclusions: Postoperatively, small bowel manipulation causes a significant and prolonged increase in spinal Fos expression, suggesting prolonged primary afferent activation. COX-2 plays a key role in this response. This activation of primary afferents may subsequently initiate inhibitory motor reflexes to the gut, contributing to postoperative ileus.