Homeostatic plasticity in the control of neuropathic pain

控制神经性疼痛的稳态可塑性

• 批准号: 8926380
• 负责人: XIAOMING JIN
• 金额: $ 30.73万
• 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/8926380
• 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; Health; 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; 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）是由伤害感受途径的主要病变引起的。该途径的过度兴奋性是由外周和中央敏化引起的，被认为是NP的神经生理标志。相应地，NP药理管理的标准范式是抑制这种过度兴奋性，这是通过临床使用某些抗癫痫药在治疗NP的情况下的例证。但是，NP对这些药物的频繁耐受性表明，应以不同的方式接近神经元过度兴奋性。由于NP中的病理生理过程表现出从传入输入的初始损失到随后的过度兴奋性和最终阵发性排放的过渡，因此可以认为这是神经系统的功能补偿反应，类似于神经元活性的体内平衡调节。因此，我们假设NP的过度兴奋性是由过度稳态补偿导致活性的初始损失而导致的，并且刺激神经元活性会抑制这种过度补偿和控制NP。我们的初步数据支持了这一假设，表明通过个体发生刺激或局灶性药物释放增强皮质神经元活性可有效控制NP动物模型的疼痛。在该项目中，我们将采用成熟的小鼠NP的瞬时脊髓缺血模型，以确定对皮质神经元的特定特定种群的受控刺激或皮质活性的药理增强是否会阻止这种进展和控制NP的进展，以及神经系统的受伤是否会诱导病理稳态调节性调节性，从而诱导cortalical corporical降低症状。个体发生刺激对神经元过度兴奋性的直接影响和机制将进一步确定。该项目的成功将确定过度稳态补偿在NP发展中的作用，并将通过刺激神经元活性来验证控制NP的新策略。建立这种no策略不仅为当前使用皮质刺激的P（例如，重复的经颅磁刺激）提供理论基础，而且还将为发现新的门打开门 通过促进神经元活性来控制NP的药物。由于其非常规的概念，创新的方法以及与公共卫生的重要相关性，因此该提案特别适合尤里卡机制。