MICA: Monocyte and macrophage manipulation for the control of chemotherapy-induced pain

慢性神经性疼痛是由损伤、糖尿病或化疗药物治疗癌症引起的神经系统损伤或疾病引起的。神经性疼痛很难治疗，目前的药物相对无效，并且通常具有显著的副作用。有效控制神经病理性疼痛可以显著改善许多患者的生活质量。特别是，用于癌症的化疗药物治疗通常导致30-40%的患者经历手和脚的疼痛。这种不希望的副作用限制了患者可以给予的癌症药物的剂量，并且是停止治疗的主要原因。因此，更好地了解化疗引起疼痛副作用的机制可以为如何预防和/或减轻这种类型的疼痛带来新的想法，并促进新药的开发。我们在研究中使用小鼠，因为当给予化疗药物时，它们的后爪也表现出疼痛相关的行为。在最近为该研究项目铺平道路的一项研究中，我们询问了长春新碱如何引起疼痛。阿贝斯汀通常用于白血病，并导致疼痛的投诉，可以发生早在第一次治疗，并可能持续无限期。同样，小鼠在长春新碱注射的第一天和随后的两周治疗期间表现出疼痛样行为。由于止痛药可以给予化疗药物的患者以防止疼痛的发展，我们专注于最初疼痛的机制。我们发现长春新碱会损伤神经周围的血管。当这种情况发生时，专门的血细胞离开血流并进入神经，在那里它们激活疼痛神经，疼痛神经将信号传递到脊髓，然后传递到大脑，感知疼痛。我们发现，通过阻止这些细胞离开血流，长春新碱引起的疼痛确实可以预防。在这个研究项目中，我们将使用另一种化疗药物紫杉醇，它也用于白血病，并分享疼痛作为一种不良副作用。我们将在小鼠中注射长春新碱或紫杉醇，以反映患者的化疗治疗。在这些模型中，我们将寻找是什么导致疼痛开始，但也保持很长一段时间。在这些小鼠模型中，我们计划识别血细胞内外的分子，这些分子可以被新型化合物靶向，以阻止它们从血液中排出，从而构成新型的疼痛治疗。我们对从哪里开始有了一个很好的想法，并计划测试药物样化合物的止痛效果，这种化合物将阻止血细胞离开血液流动。为了做到这一点，我们将与Medivir制药公司合作，该公司将设计和提供此类化合物。此外，我们将研究商业上可获得的化合物的潜在疼痛缓解作用，并通过不同的机制阻止细胞进入神经。我们研究的最终目的是提供新的信息，帮助设计新的止痛药物，从而使化疗治疗更有效地使用，没有痛苦的副作用，从而提高患者的生活质量。

Chronic neuropathic pain develops following damage or disease of the nervous system caused by injury, diabetes, or cancer treatment with chemotherapy drugs. Neuropathic pain is difficult to treat, with current drugs being relatively ineffective and often having significant side effects. Effective control of neuropathic pain may dramatically improve the quality of life of many patients. In particular, chemotherapy drug treatment for cancer often results in pain in the hands and feet experienced by 30-40% of patients. This undesired side effect limits the dose of cancer drug that patients can be given and is the main reason for stopping treatment. Therefore, a better understanding of the mechanisms by which chemotherapy treatment causes painful side effects can bring new ideas on how to prevent and/or attenuate this type of pain and facilitate the development of new medicines. We use mice in our studies as they also demonstrate pain-related behaviour in their hind paws when given chemotherapy drugs. In a recent study that paved the way to this research project, we asked how Vincristine causes pain. Vincristine is commonly used for leukemias and results in complaints of pain that can occur as early as the first treatment and may last indefinitely. Similarly, mice display pain-like behavior within the first day of vincristine injection and during a subsequent two week-treatment. As pain killers could be given to patients with the chemotherapy drug to prevent the development of pain, we focused on the mechanisms responsible for the very initial pain. We found that vincristine causes damage to blood vessels around the nerves. When this happens, specialised blood cells leave the blood flow and enter the nerve where they activate pain nerves which convey signals to the spinal cord on their way to the brain where pain is perceived. We showed that by stopping these cells leaving the blood flow, vincristine-induced pain can indeed be prevented. In this research project we will use another chemotherapy drug, paclitaxel that is also used for leukemias and shares pain as an undesirable side effect. We will inject vincristine or paclitaxel in mice in order to mirror chemotherapy treatments in patients. In these models, we will look for what causes pain to start but also to remain for very long time. In these mice models, we plan to identify molecules inside and on the outside of the blood cells that can be targeted with novel compounds to stop their exit from blood, constituting new types of pain treatment. We have a good idea of where to start and plan to test the pain-relieving effect of drug-like compounds which will stop blood cells leaving the blood flow. In order to do this, we will join forces with the pharmaceutical company Medivir which will design and provide such compounds. In addition we will examine the potential pain-relieving effect of compounds which are commercially available and will stop cells entering the nerve by a different mechanism. The ultimate aim of our research is to provide new information that will help in the design of new pain relieving medicines, thus allowing chemotherapy treatments to be used more effectively, without painful side effects, thus improving the quality of life of the patient.