Homeostatic plasticity in the control of neuropathic pain

控制神经性疼痛的稳态可塑性

• 批准号: 9236814
• 负责人: XIAOMING JIN
• 金额: $ 10万
• 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/9236814
• 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; Pharmacotherapy; 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; novel therapeutics; 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(申请人提供)：神经病理性疼痛(NP)是由伤害性通路的原发损害引起的。由外周和中枢敏化引起的这一通路的过度兴奋性被认为是NP的神经生理学特征。相应地，NP的药物治疗的标准范例是抑制这种过度兴奋性，例如临床上使用某些抗癫痫药物治疗NP。然而，NP对这些药物的频繁耐受性表明，神经元的过度兴奋性应该有不同的处理方法。由于NP的病理生理过程表现为从最初的传入丢失到随后的过度兴奋和最终的阵发性放电，因此它可能被视为神经系统的一种功能代偿反应，类似于神经元活动的稳态调节。因此，我们假设，NP潜在的超兴奋性是由于对初始活动丧失的过度稳态补偿所致，刺激神经元活动将抑制这种过度补偿并控制NP。我们的初步数据表明，通过个体发生刺激或局部药物释放来增强皮质神经元的活性在控制NP动物模型的疼痛方面是有效的，这一假设得到了我们的初步数据的支持。在这个项目中，我们将使用一个已建立的小鼠短暂性脊髓缺血模型，以确定对特定皮质神经元群体的受控个体发育刺激或皮质活动的药理学增强是否可以阻止和控制NP的进展，以及神经系统损伤是否会诱导病理性的稳态调节，从而进展为皮质的高兴奋性。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内环境平衡补偿在NP发展中的作用，并将验证一种通过刺激神经元活动来控制NP的新策略。建立这一新的策略不仅将为目前使用皮质刺激治疗P(如重复的经颅磁刺激)提供理论基础，而且将为发现新的 通过促进神经元活动来控制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，这一提议特别适合尤里卡机制。