Sodium Channel Nav1.6 in Chemotherapy-Induced Pain

钠通道 Nav1.6 在化疗引起的疼痛中的作用

• 批准号: 10507771
• 负责人: Sulayman D Dib-Hajj
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507771
• 关键词: Action Potentials; Adult; Afferent Neurons; Axon; Behavioral; Biophysics; Cancer Patient; Cannabidiol; Cannabinoids; Cellular biology; Chronic; Clinical; Clinical Research; Cutaneous; Data; Development; Disease; Dose; Dropout; Embryo; Epidiolex; Epilepsy; Esthesia; FDA approved; Fiber; Functional disorder; Future; Genetic Variation; Goals; Healthcare Systems; Ion Channel; Knock-out; Laboratories; Malignant Neoplasms; Measures; Mediating; Medical; Molecular Genetics; Motor; Mus; Musculoskeletal Pain; Nerve Fibers; Neural Conduction; Neurons; Neuropathy; Numbness; Outcome; Pain; Pain Threshold; Patients; Peripheral Nervous System Diseases; Personal Satisfaction; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Physiology; Predisposition; Prevention; Property; Records; Research Design; Research Methodology; Risk Factors; Role; Sodium; Sodium Channel; Temperature; Testing; Trigeminal Neuralgia; Variant; Vincristine; Work; base; chemotherapeutic agent; chemotherapy; chronic pain; debilitating pain; density; diabetic; duloxetine; effective therapy; gain of function; genetic risk factor; genetic variant; in vivo; mouse model; multidisciplinary; neoplasm registry; neuronal excitability; neurotransmission; non-opioid analgesic; novel; oxaliplatin; pain sensitivity; painful neuropathy; response; sciatic nerve; spontaneous pain; translational study; treatment strategy

Over the past decade, our multi-disciplinary studies combining molecular genetics, cell biology, ion channel biophysics, sensory neuron physiology, and behavioral analysis have pinpointed the role of sodium channel NaV1.6 in pain. Our goal now is to investigate the contribution of NaV1.6 to chemotherapy-induced pain and peripheral neuropathy (CIPPN), and to determine whether genetic variants of Nav1.6 can influence susceptibility to pain mediated by chemotherapeutic drugs. These studies will inform treatment options for pain and personalized, pharmacogenomics-based strategies in prescribing chemotherapy to cancer patients. Chemotherapy is frequently associated with sodium channelopathy and the development of neuropathy. Furthermore, studies implicating NaV1.6 in CIPPN show enhanced persistent and resurgent currents in DRG neurons following treatment with the chemotherapeutic agent oxaliplatin. Recent work from our lab has suggested involvement of Nav1.6 in pain induced by vincristine, another chemotherapeutic agent. However, the pathophysiology and pharmacology of vincristine-induced pain (VIP) including underlying genetic risk factors remain unclear. Our goal in this proposal is to investigate Nav1.6—an essential channel for action potential propagation in myelinated fibers—in CIPPN to: a) Establish the role of Nav1.6 in VIP; b) Inform pharmacogenomics-based chemotherapy to avert development of CIPPN; and c) Develop a novel non-opioid based treatment strategy that targets Nav1.6 We will apply the following research design and methods to achieve our goal. Specific Aim 1: Assess the contribution of Nav1.6 to VIP in vivo. Our preliminary data from embryonic knockout studies of Nav1.6 suggests a contribution by this channel to VIP. However, it is possible that compensatory mechanisms may confound observed outcomes. Here, we will knockout Nav1.6 in adult mice to assess the following metrics that can better inform future translational studies in adult subjects. Specific Aim 2: Assess genetic variations in Nav1.6 as a risk factor for VIP. Not all patients who undergo chemotherapy develop CIPPN, which suggests that genetic variations may underlie exaggerated response to chemotherapy. Our laboratory was the first to show that gain-of-function (GOF) variants of Nav1.6 can cause epilepsy, a disorder similar to neuropathic pain that reflects underlying neuronal hyperexcitability. We have also recently identified a GOF variant in NaV1.6 (Met136Val) in a patient with painful trigeminal neuralgia, which suggests that this variant may predispose the carrier to the development of disease. NaV1.6-M136V channels increase amplitude of transient and resurgent currents and increase neuronal firing. In this specific aim we will examine whether NaV1.6-M136V exacerbates VIP in a mouse model. Specific Aim 3: Assess the use of cannabinoids to ameliorate VIP. Cannabidiol (CBD) is FDA-approved for treatment of some forms of epilepsy and has been shown to block resurgent NaV1.6 currents at a concentration that spares peak transient current, and to reduce neuronal excitability. In this specific aim, we will determine whether treatment with CBD can ameliorate VIP. We will also compare the effect of CBD to FDA-approved duloxetine (Cymbalta®), which has sodium channel blocking activity and has been shown to be effective for treatment of CIPPN.

在过去的十年中，我们的多学科研究结合了分子遗传学，细胞生物学，离子通道