Mulpuri Yatendra, Tu Nguyen H, Inoue Kenji, Harden Grace, Nicholson Samuel J, Seenauth Anisa, Huang Yan, Escobar Keylin G, Moayedi Yalda, Bunnett Nigel W, Albertson Donna G, Schmidt Brian L
NYU Dentistry Translational Research Center, New York University Dentistry, New York, NY, United States.
NYU Pain Research Center, New York University, New York, NY, United States.
Front Pain Res (Lausanne). 2025 Mar 12;6:1532885. doi: 10.3389/fpain.2025.1532885. eCollection 2025.
Patients with oral cancer often experience intense functional pain due to mechanical stimulation at the cancer site. The role of mechanosensitive ion channels in oral cancer pain, such as TRPV4, is not fully understood.
Our objective was to investigate the role of Schwann cell TRPV4 in oral cancer pain.
We examined the impact of TRPV4 inhibition on oral cancer pain in NU/J and C57BL/6J mice injected with human tongue cancer cell line (HSC-3) and mouse oral cancer cell line (MOC2) in the hind paw or tongue. Mechanical and heat sensitivity were assessed using the von Frey and Hargreaves tests, respectively. TRPV4 expression and functional activity in Schwann cells were analyzed using immunohistochemistry, qRT-PCR, Ca imaging, and patch-clamp electrophysiology. The effect of TRPV4 activation on Schwann cell responses to mechanical stimulation was evaluated using a piezo stimulator. Conditioned media (CM) from TRPV4-activated Schwann cells were injected into the mouse paw to evaluate the contribution of TRPV4 in Schwann cells to mechanical hypersensitivity.
TRPV4 inhibition reduced paw cancer mechanical nociception in mice dose-dependently without affecting heat sensitivity. TRPV4 inhibition also decreased facial nociception in tongue cancer mice. TRPV4 was expressed mainly on the plasma membrane of mouse Schwann cells and activation of TRPV4 induced Ca responses and whole-cell membrane currents in human Schwann cells. Mechanoactivated currents in human Schwann cells were inhibited by the TRPV4 antagonist HC-067047. Schwann cell CM induced mechanical hypersensitivity in mice, which was blocked by pre-treatment with HC-067047.
TRPV4 activation plays a role in mediating mechanically induced pain of oral cancer.
口腔癌患者常因癌灶处的机械刺激而经历强烈的功能性疼痛。机械敏感性离子通道，如瞬时受体电位香草酸亚型4（TRPV4）在口腔癌疼痛中的作用尚未完全明确。
我们的目的是研究雪旺细胞TRPV4在口腔癌疼痛中的作用。
我们在NU/J和C57BL/6J小鼠的后爪或舌部注射人舌癌细胞系（HSC-3）和小鼠口腔癌细胞系（MOC2），检测TRPV4抑制对口腔癌疼痛的影响。分别使用von Frey试验和热辐射甩尾试验评估机械敏感性和热敏感性。采用免疫组织化学、定量逆转录聚合酶链反应（qRT-PCR）、钙离子成像和膜片钳电生理技术分析雪旺细胞中TRPV4的表达和功能活性。使用压电刺激器评估TRPV4激活对雪旺细胞机械刺激反应的影响。将TRPV4激活的雪旺细胞的条件培养基（CM）注射到小鼠爪中，以评估雪旺细胞中TRPV4对机械性超敏反应的作用。
TRPV4抑制剂量依赖性地降低了小鼠爪部癌痛的机械性伤害感受，而不影响热敏感性。TRPV4抑制还降低了舌癌小鼠的面部伤害感受。TRPV4主要表达于小鼠雪旺细胞的质膜上，TRPV4的激活诱导了人雪旺细胞中的钙离子反应和全细胞膜电流。人雪旺细胞中的机械激活电流被TRPV4拮抗剂HC-067047抑制。雪旺细胞CM诱导小鼠出现机械性超敏反应，HC-067047预处理可阻断该反应。
TRPV4激活在介导口腔癌机械诱导性疼痛中起作用。
