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

慢性神经性疼痛是由损伤、糖尿病或癌症化疗药物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，而且往往有明显的副作用。神经性疼痛的有效控制可以显著改善许多患者的生活质量。特别是，癌症的化疗药物治疗经常导致30-40%的患者出现手脚疼痛。这种意想不到的副作用限制了癌症药物的剂量，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/或减轻这种疼痛带来新的想法，并促进新药的开发。我们在研究中使用了老鼠，因为当给它们化疗药物时，它们的后爪也表现出与疼痛相关的行为。最近的一项研究为这个研究项目铺平了道路，我们询问长春新碱是如何引起疼痛的。长春新碱通常用于白血病，并导致疼痛的抱怨，可能发生在第一次治疗，并可能无限期地持续下去。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类似疼痛的行为。由于可以给化疗药物的患者服用止痛药以防止疼痛的发展，我们专注于最初疼痛的机制。我们发现长春新碱会对神经周围的血管造成损害。当这种情况发生时，专门的血细胞离开血流进入神经，在那里它们激活疼痛神经，将信号传递到脊髓，然后到达大脑，在那里感知疼痛。我们发现，通过阻止这些细胞离开血液流动，长春新碱引起的疼痛确实可以被预防。在这个研究项目中，我们将使用另一种化疗药物紫杉醇，紫杉醇也用于治疗白血病，它的副作用是疼痛。我们将在小鼠体内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，我们将寻找导致疼痛开始并持续很长时间的原因。在这些小鼠模型中，我们计划确定血细胞内外的分子，这些分子可以用新的化合物作为目标，阻止它们从血液中流出，从而构成新型的疼痛治疗。我们对从哪里开始有一个很好的想法，并计划测试药物类化合物的止痛效果，这种化合物会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，后者将设计和提供这些化合物。此外，我们还将研究市售化合物的潜在镇痛作用，这些化合物将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.