Neural Invasion Spreads Macrophage-Related Allodynia via Neural Root in Pancreatic Cancer

BACKGROUND: Neural invasion (N-inv) induces the neural damage and pain in pancreatic cancer (PCa). Benign nerve injury evokes allodynia through neuroinflammation in the neural root, which might be seen in PCa. Macrophages have the potential to release excitatory cytokines after nerve injury and so may play a role in the generation of chronic neuropathic pain. The aim of this study is to represent N-inv–induced allodynia in patients with PCa and to characterize allodynia-related neuroinflammation as macrophage accumulation on dorsal root ganglion (DRG) in the N-inv animal model (N-inv model). METHODS: Treatment-naïve patients with advanced PCa with no opioid use were enrolled in the clinical study. To evaluate allodynia, the current perception threshold on epigastric skin and pain score from questionnaire were measured. The association between the degrees of radiological N-inv and allodynia was evaluated. In the animal experiments, we used the N-inv model, which is established by the inoculation of the human PCa cell line into the left sciatic nerve of mice and mimics the invasion behavior of human PCa. The change of sensation was weekly measured at right hind paw, and the expressions of mRNA and protein were investigated on DRG at 6 weeks in the N-inv and sham models. The effect of macrophage depletion using liposome-encapsulated clodronate (Lp-CLD) was evaluated in the N-inv model. Tumor size and the degree of macrophage accumulation on DRG or around the tumor were investigated. RESULTS: In the clinical study, 43 patients were analyzed. The threshold of epigastric skin at 2000 Hz touch and pressure sensation was decreased in patients with severe N-inv, compared to patients without severe N-inv. Patients with severe N-inv showed a high pain score. In the animal experiments, the N-inv model decreased the threshold of right hind paw at 5 and 6 weeks. The macrophage-related gene expression and F4/80-positive macrophages were increased in the left DRG. Lp-CLD–induced macrophage depletion induced an increase of the threshold in the right hind paw and a decrease of CD206-positive macrophages accumulation in the left DRG. Lp-CLD had no effect for tumor size. CONCLUSIONS: The present study first showed that the N-inv–induced allodynia was spread in patients with PCa and in the N-inv model. Allodynia was related to the amount of macrophages at DRG in the N-inv model. The neuroinflammation may be a target for researching the N-inv-induced pain mechanism and developing novel analgesics. Accepted for publication November 16, 2017. Funding: Supported by Grants-in-Aid for Cancer Research and for the Third-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan; JSPS KAKENHI Grant Number 22790624; the National Cancer Center Research and Development Fund (23-A-2); Third-Term Comprehensive Control Research for Cancer from the Ministry of Health, Labour and Welfare of Japan; and Chugai Pharmacology Co, Ltd. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Shuichi Mitsunaga, MD, PhD, Division of Biomarker Discovery, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277–8577, Japan. Address e-mail to smitsuna@east.ncc.go.jp. © 2018 International Anesthesia Research Society

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