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

MICA：单核细胞和巨噬细胞操作用于控制化疗引起的疼痛

• 批准号: MR/M023893/1
• 负责人: Marzia Malcangio
• 金额: $ 43.9万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM023893%2F1
• 关键词: MICA; Monocyte; macrophage; manipulation; control

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.

慢性神经性疼痛是由于损伤、糖尿病或化疗药物癌症治疗引起的神经系统损伤或疾病而发生的。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。有效控制神经性疼痛可以显着改善许多患者的生活质量。尤其是癌症的化疗药物治疗常常会导致30-40%的患者出现手脚疼痛。这种不良副作用限制了患者可以服用的抗癌药物剂量，也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/或减轻此类疼痛并促进新药物的开发带来新的思路。我们在研究中使用小鼠，因为在给予化疗药物时，它们的后爪也表现出与疼痛相关的行为。在最近为该研究项目铺平道路的一项研究中，我们询问长春新碱如何引起疼痛。长春新碱常用于治疗白血病，并会导致患者在第一次治疗时就出现疼痛症状，并可能无限期持续。同样，小鼠在注射长春新碱的第一天和随后的两周治疗期间表现出类似疼痛的行为。由于可以给接受化疗药物的患者服用止痛药来预防疼痛的发展，因此我们重点关注导致最初疼痛的机制。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，特殊的血细胞离开血流并进入神经，在那里它们激活疼痛神经，这些神经将信号传递到脊髓，然后到达感知疼痛的大脑。我们发现，通过阻止这些细胞离开血流，确实可以预防长春新碱引起的疼痛。在这个研究项目中，我们将使用另一种化疗药物紫杉醇，它也用于治疗白血病，并且具有疼痛作为不良副作用。我们将向小鼠注射长春新碱或紫杉醇，以模拟患者的化疗治疗。在这些模型中，我们将寻找导致疼痛开始但持续很长时间的原因。在这些小鼠模型中，我们计划识别血细胞内部和外部的分子，这些分子可以用新型化合物作为目标，以阻止它们从血液中排出，从而构成新型疼痛治疗方法。我们很清楚从哪里开始，并计划测试类药物化合物的止痛效果，这些化合物可以阻止血细胞离开血流。为了做到这一点，我们将与制药公司 Medivir 合作，该公司将设计并提供此类化合物。此外，我们将研究市售化合物的潜在止痛作用，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，有助于设计新的止痛药物，从而使化疗治疗能够更有效地使用，而不产生痛苦的副作用，从而提高患者的生活质量。

项目成果

Spinal mechanisms of neuropathic pain: Is there a P2X4-BDNF controversy?

• DOI: 10.1016/j.ynpai.2017.04.001
• 发表时间: 2017-01-01
• 期刊: Neurobiology of pain (Cambridge, Mass.)
• 作者: Malcangio, Marzia

Changes in blood-spinal cord barrier permeability and neuroimmune interactions in the underlying mechanisms of chronic pain.

• DOI: 10.1097/pr9.0000000000000879
• 发表时间: 2021
• 期刊: Pain reports
• 影响因子: 4.8
• 作者: Montague-Cardoso K;Malcangio M
• 通讯作者: Malcangio M

The therapeutic potential of targeting chemokine signalling in the treatment of chronic pain.

• DOI: 10.1111/jnc.13927
• 发表时间: 2017-05
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Montague K;Malcangio M
• 通讯作者: Malcangio M

The Therapeutic Potential of Monocyte/Macrophage Manipulation in the Treatment of Chemotherapy-Induced Painful Neuropathy.

• DOI: 10.3389/fnmol.2017.00397
• 发表时间: 2017
• 期刊: Frontiers in molecular neuroscience
• 影响因子: 4.8
• 作者: Montague K;Malcangio M
• 通讯作者: Malcangio M