TRPA1 regulation of oral cancer nociception

项目摘要 口腔癌患者在癌症的原发部位遭受持续和严重的疼痛。口腔癌疼痛是 阿片类药物管理不善一小部分癌症患者不报告疼痛。口腔癌疼痛开始 并维持在肿瘤微环境（TME）中。从癌细胞释放的介质使原发性 传入神经元（伤害感受器）并且还可以增加TME中的神经元密度以产生机械， 热和化学感觉痛觉过敏。口腔癌患者报告机械性和功能性异常性疼痛， 以及热和化学过敏。这些发现在口腔癌小鼠中得到了复制 模型神经元上的瞬时受体电位（TRP）通道与口面部疼痛有关。TRP 香草素1（TRPV 1）对酸和热有反应，但对机械刺激无反应。相反，TRP锚蛋白重复序列1 TRPA 1与TRPV 1在伤害感受器的一个亚群上共表达，已经涉及机械性损伤。 异常性疼痛癌症疼痛与癌症微环境中神经密度增加有关， 提示疼痛性口腔癌TME中TRPA 1+神经元密度的增加介导了TME中TRPA 1+神经元的表达。 患者经历的机械性和功能性异常性疼痛。然而，我们的知识中有一个缺口， 关于TRPA 1在口腔癌疼痛介导中的神经生物学作用。长期目标是确定 口腔癌微环境的分子解剖学，以及有助于 口腔癌疼痛本申请的总体目标是：1）确定TRPA 1+的密度是否 TME中的纤维在报告高水平疼痛的口腔癌患者中更大，2）确定 TRPA 1对由神经元释放的介质诱发的机械异常性疼痛和热痛觉过敏的贡献 口腔癌疼痛小鼠模型中的口腔癌细胞。中心假设是口腔癌引起疼痛 （机械异常性疼痛和热痛觉过敏）是由TRPA 1对感觉神经元的敏化介导的。 该项目的基本原理是，识别由口服致敏的感觉神经元上的特异性受体， 癌症疼痛介质提供了开发口腔癌疼痛新疗法的机会， 对鸦片的依赖中心假设将通过追求两个具体目标进行测试：1）评估 TRPA 1在疼痛性和非疼痛性口腔癌患者的回顾性队列中的表达 在小鼠模型中评估TRPA 1对口腔癌伤害感受的影响。第一个目标是TRPA 1 + 将在具有最高和最低疼痛的回顾性患者队列中测量TME中的神经元密度 成绩.对于第二个目的，TRPA 1对机械和热超敏反应的影响将在一个实验室中测量。 口腔癌疼痛小鼠模型。这项研究具有创新性，因为TRPA 1对口腔粘膜的影响 癌症疼痛尚未被研究。这项研究意义重大，因为研究结果将决定 TRPA 1-口腔癌轴的拮抗作用是否有利于缓解口腔癌疼痛。

Project summary Oral cancer patients suffer persistent and severe pain at the primary site of the cancer. Oral cancer pain is poorly managed with opioids. A small subset of cancer patients do not report pain. Oral cancer pain is initiated and maintained in the tumor microenvironment (TME). Mediators released from the cancer sensitize primary afferent neurons (nociceptors) and may also increase neuronal density in the TME to produce mechanical, thermal and chemosensory hyperalgesia. Oral cancer patients report mechanical and functional allodynia, as well as thermal and chemical hypersensitivity. These findings have been replicated in oral cancer mouse models. Transient receptor potential (TRP) channels on neurons have been implicated in orofacial pain. TRP vanilloid 1 (TRPV1) responds to acid and heat, but not mechanical stimuli. By contrast, TRP ankyrin repeat 1 (TRPA1), which is co-expressed with TRPV1 on a subset of nociceptors, has been implicated in mechanical allodynia. Cancer pain is associated with increased density of nerves in the cancer microenvironment, suggesting that increased TRPA1+ neuronal density in the TME of painful oral cancers mediates the mechanical and functional allodynia experienced by patients. There is a gap in our knowledge, however, regarding the neurobiological role of TRPA1 in mediation of oral cancer pain. The long-term goal is to define the molecular anatomy of the oral cancer microenvironment, and the associated mechanisms that contribute to oral cancer pain. The overall objectives of this application are to; 1) determine whether density of TRPA1+ fibers in the TME is greater in oral cancers from patients who report high levels of pain and 2) determine the contribution of TRPA1 to mechanical allodynia and thermal hyperalgesia evoked by mediators released from oral cancer cells in a mouse model of oral cancer pain. The central hypothesis is that oral cancer induced pain (mechanical allodynia and thermal hyperalgesia) is mediated by sensitization of TRPA1 on sensory neurons. The rationale for this project is that identification of specific receptors on sensory neurons sensitized by oral cancer pain mediators provides the opportunity to develop novel therapies for oral cancer pain to reduce dependence on opioids. The central hypothesis will be tested by pursuing two specific aims: 1) Evaluate TRPA1 expression in a retrospective cohort of oral cancer patients with painful and non-painful cancers 2) Evaluate the impact of TRPA1 on oral cancer nociception in a mouse model. Under the first aim TRPA1+ neuronal density in the TME will be measured in a retrospective patient cohort with highest and lowest pain scores. For the second aim impact of TRPA1 on mechanical and thermal hypersensitivity will be measured in a mouse model of oral cancer pain. The proposed research is innovative because the impact of TRPA1 on oral cancer pain has not been studied. The proposed study is significant, because the results will determine whether antagonism of the TRPA1-oral cancer axis could be beneficial in mitigation of oral cancer pain.