Antinociceptive Mechanisms of Repetitve Motor Cortex Stimulation

重复运动皮层刺激的镇痛机制

• 批准号: 8708265
• 负责人: Li Jiang
• 金额: $ 5.6万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-14 至 2015-02-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708265
• 关键词: Aftercare; Animals; Behavior; Brain; Cell Nucleus; Cells; Chronic; Development; Electric Stimulation; Functional Magnetic Resonance Imaging; Hyperalgesia; In Vitro; Laboratories; Mechanics; Methods; Modality; Motor Cortex; Neurons; Nociception; Outcome; Pain; Pathway interactions; Patients; Pharmacological Treatment; Physiologic pulse; Plastics; Posterior Thalamic Nuclei; Preparation; Process; Rattus; Research Personnel; Research Project Grants; Resistance; Rest; Series; Slice; Spinal cord injury; Stimulus; Structure; Synapses; Synaptic Transmission; Testing; Thalamic Nuclei; Thalamic structure; Time; Withdrawal; attenuation; base; blood oxygen level dependent; chronic neuropathic pain; effective therapy; improved; insight; novel; optogenetics; painful neuropathy; postsynaptic; prevent; public health relevance; research study; response; spinal cord injury pain; spontaneous pain; zona incerta

DESCRIPTION (provided by applicant): Neuropathic pain is a common consequence of spinal cord injury (SCI). It is characterized by steady, excruciating and unrelenting pain that is resistant to conventional pharmacological treatment. An alternative modality of treatment, motor cortex stimulation (MCS), offers hope for patients with SCI-pain. However, outcomes vary widely among clinicians, and despite its potential, pain relief is only transient. Recent studies i the laboratory have illustrated a novel neuronal circuit that regulates the flow of nociceptive information from the thalamus to the cortex. At the center of this circuit is the inhibitory nucleu zona incerta (ZI) that specifically innervates higher order thalamic nuclei involved in nociceptive processing, such as the posterior thalamic nucleus (PO). In animals with SCI, pain is associated with reduced inhibition in the incerto-thalamic pathway and altered functional connectivity between the thalamus and the cortex. In addition, it was demonstrated that single treatments with effective MCS parameters reduce spontaneous pain-like behaviors in animals with SCI by restoring inhibition in the incerto- thalamic pathway. Pain reduction and restored inhibition lasts for up to 60 minutes after MCS suggesting that pain relief, albeit transient, can persist after stimulation has stopped. In a series of related preliminary experiments I tested if MCS can be manipulated to produce long-lasting, rather than transient, pain relief. I stimulated the motor cortex (M1) daily (1/day) for 10 days and found robust long-term reversal of hyperalgesia that lasts for approximately 7 days after stimulation stopped. The reversal of hyperalgesia was associated with a reduction in spontaneous activity in PO. Based on these findings, I hypothesize that repetitive MCS (rMCS) produces plastic changes in brain circuits involved in nociceptive processing and that these changes result in long-lasting pain relief. I will investigat the following aims: Aim 1: Long-term reduction in pain-like behavior after rMCS is associated with plastic changes in synaptic transmission in the M1-incerto-thalamic pathway. Aim 2: Long-term reduction in pain-like behavior after rMCS is associated with plastic changes in functional connectivity and functional activity in brain networks involved in nociceptive processing.

描述(申请人提供)：神经性疼痛是脊髓损伤(SCI)的常见后果。它的特点是持续、痛苦和无情的疼痛，对传统的药物治疗具有抵抗力。另一种治疗方式，运动皮质刺激(MCS)，为SCI疼痛患者带来了希望。然而，临床医生的结果差异很大，尽管它有潜力，但疼痛缓解只是暂时的。实验室最近的研究说明了一种新的神经元回路，它调节从丘脑到皮质的伤害性信息流动。位于该回路中心的是特定支配参与伤害性反应的丘脑高级核团的抑制性透明带核团(Zi)。 加工，如丘脑后核(PO)。在患有脊髓损伤的动物中，疼痛与内侧丘脑-丘脑通路的抑制减少和丘脑与皮质之间的功能连接改变有关。此外，研究还表明，具有有效MCS参数的单一治疗可通过恢复脊髓-丘脑通路的抑制来减少脊髓损伤动物的自发痛样行为。疼痛减轻和恢复抑制持续时间 在MCS后长达60分钟，表明疼痛缓解，尽管是短暂的，但在刺激停止后可以持续。在一系列相关的初步实验中，我测试了MCS是否可以被操纵来产生持久的、而不是短暂的疼痛缓解。我每天刺激运动皮质(M1)，连续10天，发现痛觉过敏的长期强劲逆转，在刺激停止后持续约7天。痛觉过敏的逆转与PO自发活动的减少有关。基于这些发现，我假设重复的MCS(RMCs)在涉及伤害性信息处理的大脑回路中产生可塑性变化，并且这些变化导致长期的疼痛缓解。我将研究以下目标：目的1：RMCs后疼痛行为的长期减少与M1-未明-丘脑通路突触传递的可塑性变化有关。目的2：RMCs后疼痛行为的长期减少与参与伤害性处理的大脑网络的功能连通性和功能活动的可塑性变化有关。