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

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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.