Increased Expression of 5-HT3 and NK1 Receptors in 5-Fluorouracil-Induced Mucositis in Mouse Jejunum.

Background and Objective: Although 5-fluorouracil (5-FU) is a widely used as chemotherapy agent, severe mucositis develops in approximately 80 % of patients. 5-FU-induced small intestinal mucositis can cause nausea and vomiting. The current study was designed to investigate peripheral alterations due to the 5-FU-induced mucositis of neuronal and non-neuronal 5-HT 3 and NK 1 receptor expression by immunohistochemical analysis. Methods: 5-FU was administered by i.p. injection to C57BL/6 mice. After 4 days, segments of the jejunum were removed. The specimens were analyzed by immunohistochemistry, real-time PCR, and enzyme immunoassay. Results: The numbers of 5-HT 3 receptor immunopositive cells and nerve fibers in mucosa were increased by 5-FU treatment. The 5-HT 3 receptor immunopositive cell bodies were found only in jejunal submucosa and myenteric plexus in the 5-FU-treated mice. The numbers of NK 1 receptor cells in mucosa and immunopositive expression of NK 1 receptors in deep muscular plexus were dramatically increased in 5-FU-treated mice. Real-time PCR demonstrated that 5-FU treatment significantly increased mRNA levels of 5-HT 3A, 5-HT 3B, and NK 1 receptors. The amounts of 5-HT and substance P increased after 5-FU treatment. The 5-HT 3 or NK 1 receptor immunopositive cells colocalized with both 5-HT and substance P. Furthermore, 5-HT 3 and NK 1 receptors colocalized with CD11b. Conclusions: The 5-HT 3 and NK 1 immunopositive macrophages and mucosal mast cells in lamina propria release 5-HT and substance P, which in turn activate their corresponding receptors on mucosal cells in autocrine and paracrine manners. It is assumed to result in the release of 5-HT and substance P in mucosa. [ABSTRACT FROM AUTHOR]