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

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Abstract

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-HT3 and NK1 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-HT3 receptor immunopositive cells and nerve fibers in mucosa were increased by 5-FU treatment. The 5-HT3 receptor immunopositive cell bodies were found only in jejunal submucosa and myenteric plexus in the 5-FU-treated mice. The numbers of NK1 receptor cells in mucosa and immunopositive expression of NK1 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-HT3A, 5-HT3B, and NK1 receptors. The amounts of 5-HT and substance P increased after 5-FU treatment. The 5-HT3 or NK1 receptor immunopositive cells colocalized with both 5-HT and substance P. Furthermore, 5-HT3 and NK1 receptors colocalized with CD11b.

Conclusions

The 5-HT3 and NK1 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.

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Acknowledgments

Horie received a collaborative research grant from Taiho Pharmaceutical Co. Ltd. (Tokushima, Japan). This work was also supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and The Uehara Memorial Foundation.

Conflict of interest

Syunji Horie received a collaborative research grant from Taiho Pharmaceutical Co. Ltd. (Tokushima, Japan). The remaining authors have no competing interests and have no conflict of interests.

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Authors and Affiliations

  1. Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University, 1 Gumyo, Togane, Chiba, 283-8555, Japan

    Kenjiro Matsumoto, Tomoharu Nakajima, Sae Kato, Kimihito Tashima & Syunji Horie

  2. Department of Pharmacology, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan

    Kenjiro Matsumoto, Hiroyasu Sakai, Atsunobu Sagara, Kazuhiko Arakawa & Minoru Narita

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  1. Kenjiro Matsumoto
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  2. Tomoharu Nakajima
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Correspondence to Kenjiro Matsumoto.

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Matsumoto, K., Nakajima, T., Sakai, H. et al. Increased Expression of 5-HT3 and NK1 Receptors in 5-Fluorouracil-Induced Mucositis in Mouse Jejunum. Dig Dis Sci 58, 3440–3451 (2013). https://doi.org/10.1007/s10620-013-2709-7

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