Department of Anesthesiology and Intensive Care, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, No.2 Building, 3rd Floor, Shanghai, 200438, China.
Department of Anesthesiology, 101st Hospital of CPLA, Wuxi, Jiangsu, China.
J Mol Neurosci. 2019 Oct;69(2):235-245. doi: 10.1007/s12031-019-01352-6. Epub 2019 Jun 14.
Cancer pain induced by pancreatic carcinoma is one of the most common symptoms and is difficult to endure, especially in the advanced stage. Evidence suggests that mast cells are recruited and degranulate in enteric disease-related visceral hypersensitivity. However, whether mast cells promote the visceral pain induced by pancreatic carcinoma remains unclear. Here, using toluidine blue staining and western blotting, we observed that mast cells were dramatically recruited to tissues surrounding pancreatic carcinoma, but not inside the carcinoma in patients with severe visceral pain. The levels of mast cell degranulation products, including tryptase, histamine, and nerve growth factor, were significantly increased in pericarcinoma tissues relative to their levels in normal controls, as evidenced by enzyme-linked immunosorbent assay. We determined that systemic administration of mast cell secretagogue compound 48/80 exacerbated pancreatic carcinoma-induced visceral hypersensitivity in a male BALB/c nude mouse model as assessed by measuring the hunching behavior scores and mechanical withdrawal response frequency evoked by von Frey stimulation. In contrast, the mast cell stabilizer ketotifen dose-dependently alleviated pancreatic cancer pain. In addition, we observed incomplete development of abdominal mechanical hyperalgesia and hunching behavior in mast cell-deficient mice with pancreatic carcinoma. However, ketotifen did not further attenuate visceral hypersensitivity in mast cell-deficient mice with carcinoma. Finally, we confirmed that intraplantar injection of pericarcinoma supernatants from BALB/c nude mice but not mast cell-deficient mice caused acute somatic nociception. In conclusion, our findings suggest that mast cells contribute to pancreatic carcinoma-induced visceral hypersensitivity through enrichment and degranulation in pericarcinoma tissues. The inhibition of mast cell degranulation may be a potential strategy for the therapeutic treatment of pancreatic carcinoma-induced chronic visceral pain.
胰腺癌引起的癌痛是最常见的症状之一，尤其在晚期难以忍受。有证据表明，肥大细胞在与肠道疾病相关的内脏感觉过敏中被募集和脱颗粒。然而，肥大细胞是否促进胰腺癌引起的内脏疼痛尚不清楚。在这里，我们通过甲苯胺蓝染色和western blot 观察到，在严重内脏疼痛的患者中，肥大细胞大量募集到胰腺癌周围的组织中，但不在癌内。酶联免疫吸附试验显示，与正常对照组相比，癌周组织中肥大细胞脱颗粒产物，包括胰蛋白酶、组织胺和神经生长因子的水平显著升高。我们确定系统给予肥大细胞分泌剂化合物 48/80 可加剧 BALB/c 裸鼠胰腺癌模型的内脏高敏感，通过测量 von Frey 刺激引起的蜷缩行为评分和机械撤回反应频率来评估。相反，肥大细胞稳定剂酮替芬剂量依赖性地缓解胰腺癌疼痛。此外，我们观察到胰腺癌肥大细胞缺陷小鼠的腹部机械性痛觉过敏和蜷缩行为发育不完全。然而，酮替芬并没有进一步减弱肥大细胞缺陷型癌小鼠的内脏高敏感。最后，我们证实了从 BALB/c 裸鼠而不是肥大细胞缺陷型小鼠的癌周上清液中注射可引起急性躯体痛觉过敏。总之，我们的研究结果表明，肥大细胞通过在癌周组织中富集和脱颗粒参与胰腺癌引起的内脏高敏感。抑制肥大细胞脱颗粒可能是治疗胰腺癌引起的慢性内脏疼痛的潜在策略。
