TRPA1 regulation of oral cancer nociception

项目总结 口腔癌患者在癌的原发部位持续剧烈的疼痛。口腔癌疼痛是 阿片类药物管理不善。一小部分癌症患者不会报告疼痛。口腔癌疼痛始发 并维持在肿瘤微环境(TME)中。从癌症中释放的介质使原发肿瘤变得敏感 传入神经元(伤害性感受器)，也可能增加TME内的神经元密度，以产生机械， 热和化学敏感型痛觉过敏。口腔癌患者报告机械性和功能性痛觉异常，AS 以及热和化学过敏性。这些发现已经在口腔癌小鼠身上重复。 模特们。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(TRPV1)对酸和热有反应，但不对机械刺激有反应。相比之下，Trp Anyrin Repeat 1 (TRPA1)与TRPV1在伤害性感受器的子集上共表达，已被认为与机械性 超感痛症。癌症疼痛与癌症微环境中神经密度的增加有关， 提示口腔癌疼痛患者TME中TRPA1+神经元密度的增加介导了 患者所经历的机械性和功能性异位痛觉。然而，我们的知识中存在一个缺口， 关于TRPA1在调节口腔癌疼痛中的神经生物学作用。长期目标是定义 口腔癌微环境的分子解剖学及其相关机制 口腔癌疼痛。本申请的总体目标是：1)确定TRPA1+的密度 在口腔癌患者中，TME中的纤维较多，这些患者报告的疼痛程度和2)决定了 TRPA1在释放的介质引起的机械性痛觉过敏和热痛敏中的作用 口腔癌细胞在小鼠口腔癌疼痛模型中的应用。中心假设是口腔癌引起疼痛 (机械性痛觉过敏和热痛觉过敏)是由感觉神经元上的TRPA1敏化介导的。 这个项目的基本原理是识别口服致敏的感觉神经元上的特定受体 癌症疼痛介质为开发新的口腔癌疼痛疗法提供了机会，以减少 对阿片类药物的依赖。核心假设将通过追求两个具体目标来检验：1)评估 TRPA1在口腔癌疼痛和非疼痛癌症患者中的表达 评价TRPA1对口腔癌小鼠伤害性感受的影响。根据第一个目标，TRPA1+ 将在疼痛程度最高和最低的回溯性患者队列中测量TME中的神经元密度 得分。对于第二个目标，TRPA1对机械和热过敏的影响将在 小鼠口腔癌疼痛模型。拟议的研究具有创新性，因为TRPA1对口腔的影响 癌症疼痛尚未被研究过。这项拟议的研究意义重大，因为结果将决定 拮抗TRPA1-口腔癌轴是否有利于减轻口腔癌痛。

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.