Homeostatic plasticity in the control of neuropathic pain

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病变引起的。外周和中枢致敏导致的该通路的高兴奋性被认为是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高兴奋性，如临床使用某些抗癫痫药物治疗NP的例子。然而，NP对这些药物的难治性表明，应该从不同的角度来看待神经元的高兴奋性。由于NP的病理生理过程表现为从传入输入的初始丢失到随后的高兴奋性和最终的阵发性放电的转变，因此可以将其视为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，我们假设NP背后的超兴奋性是由于对初始活动丧失的过度稳态补偿，刺激神经元活动将抑制这种过度补偿并控制NP。这一假设得到了我们的初步数据的支持，这些数据表明，通过个体发生刺激或局灶性药物释放来增强皮质神经元的活动，可以有效地控制NP动物模型的疼痛。在本项目中，我们将采用一种完善的小鼠NP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生刺激或皮质活性的药理增强是否会阻止NP的进展并控制NP，以及神经系统损伤是否会诱导病理性稳态调节，从而发展为皮质亢进。个体源性刺激对神经元高兴奋性的直接作用及其机制有待进一步研究。该项目的成功将确立过度内平衡补偿在NP发展中的作用，并将验证通过刺激神经元活动来控制NP的新策略。建立这一策略不仅将为目前使用皮层刺激治疗P（例如，重复经颅磁刺激）提供理论基础，而且将为发现新的治疗方法打开大门

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.