Role of Primary Sensory Neuron CaMKII Signaling in Regulation of Pain

初级感觉神经元 CaMKII 信号传导在疼痛调节中的作用

• 批准号: 10656886
• 负责人: Andy Hudmon
• 金额: $ 62.12万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656886
• 关键词: Absence of pain sensation; Action Potentials; Acute; Address; Adult; Afferent Neurons; Analgesics; Anatomy; Animal Model; Binding; Biological Assay; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calcium Signaling; Calmodulin; Cell model; Cell physiology; Cells; Central Nervous System; Chronic; Clinical; Cytoskeleton; Dependovirus; Development; Dinoprostone; Dissociation; Effectiveness; Electrodes; Engineering; Environment; Exposure to; Female; Fiber; Foundations; Generations; Genetic; Genetic Transcription; Histologic; Hyperalgesia; In Situ; In Vitro; Injections; Iodoacetates; Knowledge; Learning; Maintenance; Measures; Membrane; Memory; Molecular; Nerve Growth Factors; Neurons; Opioid; Pain; Pathway interactions; Patients; Pattern; Peripheral; Peripheral Nervous System; Phosphorylation; Phosphotransferases; Pre-Clinical Model; Process; Protein Kinase; Protein-Serine-Threonine Kinases; Proteins; Public Health; Rattus; Regulation; Research; Role; Route; Safety; Sample Size; Second Messenger Systems; Sensory; Signal Transduction; Site; Slice; Spinal Ganglia; Structure of tibial nerve; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic; Therapeutic Uses; Transgenes; Translations; Trigeminal System; Up-Regulation; Viral; Whole-Cell Recordings; Work; abuse liability; addiction; adeno-associated viral vector; chronic pain; chronic pain management; chronic pain relief; dorsal horn; experimental study; in vivo; inhibitor; insight; male; monomer; nerve injury; neuroregulation; non-opioid analgesic; novel; novel therapeutics; osteoarthritis pain; pain model; pain reduction; painful neuropathy; pharmacologic; presynaptic; programs; sensor; side effect; spinal nerve posterior root; success; therapeutic development; transgene expression; transmission process; treatment strategy

Summary/Abstract Chronic pain is a major public health challenge that is inadequately addressed. While opioids afford acute relief, their chronic use often leads to addiction and intolerable side-effects in patients. We and others have shown that dorsal root ganglion (DRG) field stimulation blocks pain in patients and pre-clinical models, which provides an opportunity to directly identify the underlying mechanisms of neuropathic pain, and hopefully to find novel non- opioid approaches to reduce pain. One protein we have identified to be a valid target is the calcium/calmodulin (Ca2+/CaM)-dependent protein kinase (CaMKII), a critical regulator of the analgesic effects of DRG stimulation. CaMKII is able to orchestrate diverse cellular functions to match required changes in excitable cell activity. Knowledge on the role of CaMKII in regulating peripheral nervous system and primary sensory neuron function is limited. Prior studies examining its role in pain have consistently associated it with mechanisms generating pain rather than analgesia, based on experiments exposing both the peripheral nervous system and the central nervous system to pharmacological inhibitors of CaMKII signaling. In contrast, our promising initial findings ex- amining CaMKII signaling specifically in peripheral sensory neurons, i.e., those with their cell bodies in the DRGs, indicate that painful conditions induced in preclinical models are associated with deficient sensory neuron CaMKII signaling. Selective inhibition of peripheral sensory neuron CaMKII at the level of the DRG produces hyperalgesia, while amplification of sensory neuron CaMKII signaling by molecular or electrical neuromodulation approaches produces potent analgesia. We have developed viral approaches highly suited for selectively tar- geting CaMKII in primary sensory neurons, and are proposing the following Aims to test the hypothesis that reduced activity of CaMKII in peripheral sensory neurons drives the maintenance of chronic pain, and increasing activity of CaMKII in DRG will alleviate chronic pain. Specifically, Aim 1. Establish the role of peripheral sensory neuron CaMKII activity in suppressing pain. Aim 2. Identify the anatomic site of action for sensory neuron CaMKII analgesia. Aim 3. Determine molecular mechanisms of CaMKII inactivation in animal and cell models of pain. Completion of the proposed project will generate new insights on how sensory neuron CaMKII regulates the development of neuropathic and osteoarthritic pain, along with proof-of-concept foundations for developing novel opioid-free treatments based on selective reversal of chronic pain-induced down-regulated CaMKII activity.

总结/摘要 慢性疼痛是一个重大的公共卫生挑战，但没有得到充分解决。虽然阿片类药物提供急性缓解， 它们的长期使用常常导致患者成瘾和无法忍受的副作用。我们和其他人已经证明， 背根神经节（DRG）场刺激阻断患者和临床前模型中的疼痛，这提供了一种 有机会直接识别神经性疼痛的潜在机制，并希望找到新的非神经性疼痛。 阿片类药物来减轻疼痛。我们已经确定的一种有效靶蛋白是钙/钙调素 (Ca2+/CaM）依赖性蛋白激酶（CaMKII），其是DRG刺激的镇痛作用的关键调节剂。 CaMKII能够协调不同的细胞功能，以匹配可兴奋细胞活性所需的变化。 对CaMK Ⅱ在调节周围神经系统和初级感觉神经元功能中作用的认识 是有限的。先前的研究检查其在疼痛中的作用，一直将其与产生疼痛的机制联系起来。 疼痛而不是镇痛，基于暴露外周神经系统和中枢神经系统的实验， 神经系统对CaMKII信号传导的药理学抑制剂。相比之下，我们有希望的初步发现， 在外周感觉神经元中特异性地胺化CaMKII信号传导，即，那些细胞体位于背根神经节的人， 表明在临床前模型中诱导疼痛状况与感觉神经元缺陷有关 CaMKII信号传导。在DRG水平选择性抑制外周感觉神经元CaMKII， 痛觉过敏，同时通过分子或电神经调节放大感觉神经元CaMKII信号传导 方法产生有效的镇痛。我们已经开发出非常适合选择性靶向的病毒方法， 在初级感觉神经元中获得CaMKII，并提出以下目的来检验假设， 外周感觉神经元中CaMKII活性的降低驱动慢性疼痛的维持， DRG中CaMKII的活性将减轻慢性疼痛。具体来说，目标1。建立外周感觉的作用 神经元CaMKII活性抑制疼痛。目标2.识别感觉神经元CaMKII作用的解剖部位 analgesia.目标3.确定疼痛的动物和细胞模型中CaMKII失活的分子机制。 该项目的完成将产生关于感觉神经元CaMKII如何调节神经元的新见解。 神经性和骨关节炎疼痛的发展，沿着开发新的 基于慢性疼痛诱导的下调CaMKII活性的选择性逆转的无阿片类药物治疗。