Bertozzi Mariana M, Saraiva-Santos Telma, Zaninelli Tiago H, Pinho-Ribeiro Felipe A, Fattori Victor, Staurengo-Ferrari Larissa, Ferraz Camila R, Domiciano Talita P, Calixto-Campos Cassia, Borghi Sergio M, Zarpelon Ana C, Cunha Thiago M, Casagrande Rubia, Verri Waldiceu A
Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil.
Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Brain Sci. 2022 Sep 15;12(9):1247. doi: 10.3390/brainsci12091247.
We standardized a model by injecting Ehrlich tumor cells into the paw to evaluate cancer pain mechanisms and pharmacological treatments. Opioid treatment, but not cyclooxygenase inhibitor or tricyclic antidepressant treatments reduces Ehrlich tumor pain. To best use this model for drug screening it is essential to understand its pathophysiological mechanisms. Herein, we investigated the contribution of the transient receptor potential cation channel subfamily V member 1 (TRPV1) in the Ehrlich tumor-induced pain model. Dorsal root ganglia (DRG) neurons from the Ehrlich tumor mice presented higher activity (calcium levels using fluo-4 fluorescent probe) and an increased response to capsaicin (TRPV1 agonist) than the saline-injected animals (p < 0.05). We also observed diminished mechanical (electronic von Frey) and thermal (hot plate) hyperalgesia, paw flinching, and normalization of weight distribution imbalance in TRPV1 deficient mice (p < 0.05). On the other hand, TRPV1 deficiency did not alter paw volume or weight, indicating no significant alteration in tumor growth. Intrathecal injection of AMG9810 (TRPV1 antagonist) reduced ongoing Ehrlich tumor-triggered mechanical and thermal hyperalgesia (p < 0.05). Therefore, the contribution of TRPV1 to Ehrlich tumor pain behavior was revealed by genetic and pharmacological approaches, thus, supporting the use of this model to investigate TRPV1-targeting therapies for the treatment of cancer pain.
我们通过将艾氏腹水癌细胞注射到爪部来标准化一种模型，以评估癌症疼痛机制和药物治疗。阿片类药物治疗可减轻艾氏腹水癌疼痛，但环氧化酶抑制剂或三环类抗抑郁药治疗则无此效果。为了将该模型最佳地用于药物筛选，了解其病理生理机制至关重要。在此，我们研究了瞬时受体电位阳离子通道亚家族V成员1（TRPV1）在艾氏腹水癌诱导的疼痛模型中的作用。与注射生理盐水的动物相比，艾氏腹水癌小鼠的背根神经节（DRG）神经元表现出更高的活性（使用fluo-4荧光探针检测钙水平）以及对辣椒素（TRPV1激动剂）的反应增强（p<0.05）。我们还观察到，TRPV1基因敲除小鼠的机械性（电子von Frey法）和热性（热板法）痛觉过敏、爪部退缩以及体重分布失衡的正常化均有所减轻（p<0.05）。另一方面，TRPV1基因敲除并未改变爪部体积或体重，表明肿瘤生长无显著变化。鞘内注射AMG9810（TRPV1拮抗剂）可减轻艾氏腹水癌引发的持续性机械性和热性痛觉过敏（p<0.05）。因此，通过遗传学和药理学方法揭示了TRPV1对艾氏腹水癌疼痛行为的作用，从而支持使用该模型来研究针对TRPV1的疗法治疗癌症疼痛。
