Graduate Program in Pharmacology, Federal University of Santa Maria (UFSM), Santa Maria, Rio Grande do Sul, Brazil.
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
Int J Cancer. 2019 Jan 15;144(2):355-365. doi: 10.1002/ijc.31911. Epub 2018 Oct 30.
There is a major, unmet need for the treatment of cancer pain, and new targets and medicines are required. The transient receptor potential ankyrin 1 (TRPA1), a cation channel expressed by nociceptors, is activated by oxidizing substances to mediate pain-like responses in models of inflammatory and neuropathic pain. As cancer is known to increase oxidative stress, the role of TRPA1 was evaluated in a mouse model of cancer pain. Fourteen days after injection of B16-F10 murine melanoma cells into the plantar region of the right hind paw, C57BL/6 mice exhibited mechanical and thermal allodynia and thigmotaxis behavior. While heat allodynia was partially reduced in TRP vanilloid 1 (TRPV1)-deficient mice, thigmotaxis behavior and mechanical and cold allodynia were absent in TRPA1-deficient mice. Deletion of TRPA1 or TRPV1 did not affect cancer growth. Intrathecal TRPA1 antisense oligonucleotides and two different TRPA1 antagonists (HC-030031 or A967079) transiently attenuated thigmotaxis behavior and mechanical and cold allodynia. A TRPV1 antagonist (capsazepine) attenuated solely heat allodynia. NADPH oxidase activity and hydrogen peroxide levels were increased in hind paw skin 14 days after cancer cell inoculation. The antioxidant, α-lipoic acid, attenuated mechanical and cold allodynia and thigmotaxis behavior, but not heat allodynia. Whereas TRPV1, via an oxidative stress-independent pathway, contributes partially to heat hypersensitivity, oxidative stress-dependent activation of TRPA1 plays a key role in mediating thigmotaxis behavior and mechanical and cold allodynia in a cancer pain model. TRPA1 antagonists might be beneficial in the treatment of cancer pain.
癌症疼痛的治疗存在重大未满足的需求，需要新的靶点和药物。瞬时受体电位锚蛋白 1（TRPA1）是一种表达于伤害感受器的阳离子通道，可被氧化物质激活，从而介导炎症和神经病理性疼痛模型中的痛觉样反应。由于已知癌症会增加氧化应激，因此评估了 TRPA1 在癌症疼痛小鼠模型中的作用。在右后爪足底区域注射 B16-F10 黑色素瘤细胞 14 天后，C57BL/6 小鼠表现出机械性和热感觉过敏以及触诱发癖行为。虽然 TRPV1 缺陷型小鼠的热感觉过敏部分减轻，但 TRPA1 缺陷型小鼠的触诱发癖行为以及机械性和冷感觉过敏均不存在。TRPA1 或 TRPV1 的缺失并不影响癌症的生长。鞘内给予 TRPA1 反义寡核苷酸和两种不同的 TRPA1 拮抗剂（HC-030031 或 A967079）可短暂减轻触诱发癖行为以及机械性和冷感觉过敏。TRPV1 拮抗剂（辣椒素）仅减轻热感觉过敏。癌症细胞接种 14 天后，后爪皮肤中的 NADPH 氧化酶活性和过氧化氢水平增加。抗氧化剂 α-硫辛酸减轻了机械性和冷感觉过敏以及触诱发癖行为，但不能减轻热感觉过敏。TRPV1 通过一种氧化应激非依赖性途径部分参与热过敏，而氧化应激依赖性的 TRPA1 激活在介导癌症疼痛模型中的触诱发癖行为以及机械性和冷感觉过敏中发挥关键作用。TRPA1 拮抗剂可能有益于癌症疼痛的治疗。
