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/文摘