• Kiichiro Yamaguchi, Kentaro Ono, Suzuro Hitomi, Misa Ito, Tomotaka Nodai, Tetsuya Goto, Nozomu Harano, Seiji Watanabe, Hiromasa Inoue, Kanako Miyano, Yasuhito Uezono, Motohiro Matoba, and Kiyotoshi Inenaga.
• Division of Physiology, Kyushu Dental University, Fukuoka, Japan Division of Dental Anesthesiology, Kyushu Dental University, Fukuoka, Japan Department of Anatomy for Oral Science, Kagoshima University, Kagoshima, Japan Department of Oral Health Management, Kyushu Dental University, Fukuoka, Japan Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan Department of Palliative Care, Japanese Red Cross Medical Center, Tokyo, Japan.
• Pain. 2016 May 1; 157 (5): 1004-1020.

AbstractIn many patients with cancer, chemotherapy-induced severe oral ulcerative mucositis causes intractable pain, leading to delays and interruptions in therapy. However, the pain mechanism in oral ulcerative mucositis after chemotherapy has not been extensively studied. In this study, we investigated spontaneous pain and mechanical allodynia in a preclinical model of oral ulcerative mucositis after systemic administration of the chemotherapy drug 5-fluorouracil, using our proprietary pain assay system for conscious rats. 5-Fluorouracil caused leukopenia but did not induce pain-related behaviors. After 5-fluorouracil administration, oral ulcers were developed with topical acetic acid treatment. Compared with saline-treated rats, 5-fluorouracil-exposed rats showed more severe mucositis with excessive bacterial loading due to a lack of leukocyte infiltration, as well as enhancements of spontaneous pain and mechanical allodynia. Antibacterial drugs, the lipid A inhibitor polymyxin B and the TRPV1/TRPA1 channel pore-passing anesthetic QX-314, suppressed both the spontaneous pain and the mechanical allodynia. The cyclooxygenase inhibitor indomethacin and the TRPV1 antagonist SB-366791 inhibited the spontaneous pain, but not the mechanical allodynia. In contrast, the TRPA1 antagonist HC-030031 and the N-formylmethionine receptor FPR1 antagonist Boc MLF primarily suppressed the mechanical allodynia. These results suggest that 5-fluorouracil-associated leukopenia allows excessive oral bacterial infection in the oral ulcerative region, resulting in the enhancement of spontaneous pain through continuous TRPV1 activation and cyclooxygenase pathway, and mechanical allodynia through mechanical sensitization of TRPA1 caused by neuronal effects of bacterial toxins. These distinct pain mechanisms explain the difficulties encountered with general treatments for oral ulcerative mucositis-induced pain in patients with cancer and suggest more effective approaches.

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