Homeostatic plasticity in the control of neuropathic pain

控制神经性疼痛的稳态可塑性

• 批准号: 8797055
• 负责人: XIAOMING JIN
• 金额: $ 31.2万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8797055
• 关键词: Affect; Animal Model; Antiepileptic Agents; Area; Behavior; Bicuculline; Brain; Calcium Signaling; Cell Nucleus; Clinical; Data; Deafferentation procedure; Development; Drug Controls; Drug usage; Employment; Excitatory Synapse; Exhibits; Financial compensation; Frequencies; Goals; Hindlimb; In Vitro; Injury; Label; Modeling; Mus; Nerve; Nervous System Trauma; Nervous system structure; Neurologic; Neurons; Nociception; Pain; Pain management; Pathogenesis; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacological Treatment; Play; Population; Primary Lesion; Process; Public Health; Quality of life; Recovery; Refractory; Regulation; Research Project Grants; Research Technics; Role; Sensory; Slice; Somatosensory Cortex; Spinal Cord Ischemia; Spinal cord injury; Structure of tibial nerve; Synapses; Testing; Thalamic structure; base; central pain; central sensitization; effective therapy; hippocampal pyramidal neuron; in vivo; innovation; midbrain central gray substance; nerve injury; neuron loss; neuronal excitability; neurophysiology; novel strategies; optogenetics; painful neuropathy; patch clamp; prevent; public health relevance; receptor; repetitive transcranial magnetic stimulation; research study; response; somatosensory; success; treatment strategy; zona incerta

DESCRIPTION (provided by applicant): Neuropathic pain (NP) is caused by a primary lesion of the nociceptive pathway. Hyperexcitability of this pathway resulting from peripheral and central sensitization is believed to be the neurophysiological hallmark of NP. Correspondingly, the standard paradigm of pharmacological management of NP is to suppress this hyperexcitability, as exemplified by the clinical use of certain antiepileptic drugs for the treatment of NP. However, the frequent refractoriness of NP to these drugs suggests that neuronal hyperexcitability should be approached differently. Because the pathophysiological process in NP exhibits a transition from an initial loss of afferent input to subsequent hyperexcitability and eventual paroxysmal discharges, it may be regarded as a functional compensatory response of the nervous system, similar to homeostatic regulation of neuronal activity. Therefore, we hypothesize that the hyperexcitability underlying NP results from excessive homeostatic compensation to the initial loss of activity and that stimulating neuronal activity will suppress this overcompensation and control NP. This hypothesis is supported by our preliminary data showing that enhancing cortical neuronal activity by either ontogenetic stimulation or focal drug release is effective in controlling pain in animal models of NP. In this project, we will employ a well-established transient spinal cord ischemia model of NP in mice to determine whether controlled ontogenetic stimulation of specific populations of cortical neurons or pharmacological enhancement of cortical activity will prevent this progression and control NP, and whether injury of the nervous system will induce pathological homeostatic regulation, which progresses to cortical hyperexcitability. The direct effect and mechanism of ontogenetic stimulation on neuronal hyperexcitability will be further determined. The success of this project will establish the role of excessive homeostatic compensation in the development of NP and will verify a novel strategy for controlling NP by stimulating neuronal activity. Establishing this nove strategy not only will provide a theoretical basis for the current use of cortical stimulation for P (e.g., repetitive transcranial magnetic stimulation), but also will open a door for discovering new drugs for controlling NP by promoting neuronal activity. Because of its unconventional concept, innovative approach, and significant relevance to public health, this proposal is particularly suited to the EUREKA mechanism.

描述（由申请人提供）：神经性疼痛（NP）是由伤害性通路的原发性损伤引起的。由外周和中枢致敏引起的该通路的过度兴奋被认为是NP的神经生理学标志。相应地，NP的药理学管理的标准范例是抑制这种过度兴奋性，如某些抗癫痫药物用于治疗NP的临床使用所例示的。然而，NP对这些药物的频繁无效表明神经元过度兴奋应该以不同的方式处理。由于NP的病理生理过程表现出从最初的传入输入损失到随后的过度兴奋和最终的阵发性放电的过渡，它可以被认为是神经系统的功能性代偿反应，类似于神经元活动的稳态调节。因此，我们推测，过度兴奋的基础NP的结果从过度的稳态补偿的初始活动的损失，刺激神经元的活动将抑制这种过度补偿和控制NP。我们的初步数据表明，无论是个体发育刺激或局灶性药物释放增强皮层神经元的活动是有效的，在控制疼痛的NP的动物模型支持这一假设。在这个项目中，我们将采用一个完善的短暂的脊髓缺血模型的NP小鼠，以确定是否控制个体发育刺激特定群体的皮质神经元或药理学增强的皮质活动将防止这种进展和控制NP，以及是否损伤的神经系统将诱导病理性稳态调节，发展到皮质兴奋过度。个体发育刺激对神经元超兴奋性的直接影响及其机制有待进一步研究。该项目的成功将确立过度稳态补偿在NP发展中的作用，并将验证通过刺激神经元活动控制NP的新策略。建立这种新的策略不仅将为目前使用皮层刺激P（例如，重复经颅磁刺激），而且还将为发现新的 通过促进神经元活性来控制NP的药物。由于其非传统的概念、创新的方法和与公共卫生的重大相关性，该提案特别适合尤里卡机制。