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.

摘要/摘要 慢性疼痛是不足以应对的主要公共卫生挑战。虽然阿片类药物可以缓解急性，但 它们的长期使用通常会导致患者成瘾和无法忍受的副作用。我们和其他人表明 背根神经节（DRG）场刺激阻止了患者和临床前模型的疼痛，这提供了一个 有机会直接识别神经性疼痛的潜在机制，并希望找到新颖的非 - 阿片类药物减轻疼痛的方法。我们确定为有效靶标的一种蛋白质是钙/钙调蛋白 （CA2+/CAM）依赖性蛋白激酶（CAMKII），这是DRG刺激的镇痛作用的关键调节剂。 CAMKII能够协调各种细胞功能，以匹配激发细胞活性所需的变化。 关于CAMKII在调节周围神经系统和主要感觉神经元功能的知识 有限。先前研究其在疼痛中的作用的研究始终将其与产生的机制相关联 疼痛而不是镇痛，基于实验暴露于周围神经系统和中央 神经系统对CAMKII信号传导的药理抑制剂。相比之下，我们有希望的初始发现 在周围感觉神经元中特别填充CAMKII信号传导，即DRG中的细胞体的信号， 表明临床前模型中引起的疼痛状况与不足的感觉神经元有关 CAMKII信号。在DRG水平上对周围感觉神经元CAMKII的选择性抑制会产生 Hypergersia，而分子或电神经调节的感觉神经元CAMKII信号的扩增 方法会产生有效的镇痛。我们已经开发了非常适合有选择性焦油的病毒方法 在原发性感觉神经元中获取CAMKII，并提出以下目的，以检验以下假设 CAMKII在周围感觉神经元中的活性减少了慢性疼痛的维持，并增加 CAMKII在DRG中的活动会减轻慢性疼痛。具体而言，目标1。确定外围感觉的作用 神经元CAMKII活性在抑制疼痛中。目标2。确定感官神经元CAMKII的解剖作用部位 镇痛。目标3。确定动物和细胞模型中CaMKII失活的分子机制。 拟议项目的完成将产生有关感官神经元如何调节的新见解 神经性和骨关节炎疼痛的发展，以及概念验证基础，用于发展新颖的基础 基于慢性疼痛引起的下调的CAMKII活性的选择性逆转的无阿片治疗。