Modulation of the prefrontal cortical network in neuropathic pain

神经性疼痛中前额皮质网络的调节

• 批准号: 10533432
• 负责人: MARCO MARTINA
• 金额: $ 1.36万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533432
• 关键词: Acetylcholine; Acute; Affect; Analgesics; Animals; Attention; Behavior; Behavioral; Biological Process; Cholinergic Receptors; Cognitive; Control Animal; Data; Decision Making; Drug Delivery Systems; Drug Prescriptions; Electrophysiology (science); Emotional; Female; Genetic; Goals; Health Care Costs; High Prevalence; Impaired cognition; Impairment; Individual; Interneurons; Laboratories; Light; Medial; Mediating; Medical; Modeling; Molecular; Muscarinic M1 Receptor; Muscarinics; Neurobehavioral Manifestations; Neurobiology; Neurons; Opioid; Opioid abuser; Output; Pain; Pain management; Patients; Pharmacological Treatment; Pharmacology; Phenotype; Positioning Attribute; Prefrontal Cortex; Price; Productivity; Pyramidal Cells; Rattus; Risk; Rodent Model; Role; Sensory; Shapes; Short-Term Memory; Signal Transduction; Slice; Spinal; Symptoms; Techniques; Testing; Work; addiction; antagonist; basal forebrain; base; behavior test; cholinergic; chronic pain; chronic pain management; cognitive performance; cognitive task; cost estimate; economic cost; effective therapy; emotional symptom; hippocampal pyramidal neuron; in vivo; insight; male; nerve injury; neurobiological mechanism; non-opioid analgesic; optogenetics; pain perception; painful neuropathy; patch clamp; prescription opioid; receptor; sex; side effect; socioeconomics; spared nerve; success; virtual

Summary The neurobiological basis of chronic pain is poorly understood and no scientifically validated therapies exist for such condition. Yet, chronic pain has an enormous socio-economic price, estimated to reach US$ 635 billion annually in healthcare costs and lost productivity. To make things worse, the majority of opioid abusers begin their addiction with prescription medications for chronic pain. Consequently, the search for new, non-opioid, pharmacological treatments for chronic pain constitutes one of the most urgent unmet medical needs. Beside its sensory symptoms, chronic pain is characterized by impairment of cognitive tasks such as attention and working memory, which depend on cholinergic modulation of medial prefrontal cortex (mPFC). Accordingly, mPFC deactivation was found to have a causal role for the neuropathic pain phenotype, and our preliminary data show that excitatory cholinergic modulation is severely impaired in mPFC pyramidal neurons of male rats. Yet, the precise mechanisms mediating the mPFC deactivation, how this deactivation influences pain perception and cognitive performance, and whether it similarly impacts males and females remain largely unknown. Our preliminary data show that a current mediated by the M1 receptor is critical for mPFC pyramidal cell excitability and is strongly reduced in neuropathic pain; our overarching hypothesis is that impaired cholinergic modulation of the mPFC represents a major mechanism of mPFC deactivation in neuropathic pain and mediates several of the sensory, cognitive and emotional symptoms. In particular, we hypothesize that in neuropathic pain: (1) cholinergic modulation of mPFC activity is disrupted and this critically contributes to the global mPFC deactivation in both sexes; (2) blockade of M1-mediated mPFC excitation is sufficient to mimic, at least in part, the neuropathic pain phenotype; (3) pharmacological manipulations that counterbalance the cholinergic disruption and restore mPFC output ameliorate cognitive and sensory symptoms of neuropathic pain. To test these hypotheses we will take advantage of the Spared-Nerve-Injury (SNI) model of neuropathic pain to pursue two specific aims. In Aim 1 we will combine optogenetic activation of individual cholinergic inputs, patch clamp recordings in acute slices and PCR analysis, to test the hypothesis that impaired cholinergic modulation contributes to the global mPFC deactivation, to determine the identity of the receptors involved, and to dissect the relative impact of cholinergic inputs from local interneurons and from the basal forebrain on mPFC activity in both females and males. In Aim 2 we will test the behavioral effects of impaired mPFC cholinergic modulation. We will use in-vivo chemogenetic and pharmacological modulation of the mPFC to reverse the SNI phenotype. We obtained preliminary data showing that enhancing mPFC excitability through pharmacological antagonism of the 5HT1a receptor has potent analgesic effects. Conversely, we will also investigate whether blockade of M1-mediated mPFC excitation in naive animals is sufficient to mimic the SNI phenotype. Our work will thus identify new potential targets for non-opioid neuropathic pain treatment.

总结 慢性疼痛的神经生物学基础知之甚少，也没有科学有效的治疗方法。 这样的条件。然而，慢性疼痛具有巨大的社会经济代价，估计达到6，350亿美元 每年的医疗成本和生产力损失。更糟糕的是，大多数阿片类药物滥用者开始 他们对治疗慢性疼痛的处方药上瘾。因此，寻找新的，非阿片类药物， 慢性疼痛的药物治疗构成了最迫切的未满足的医疗需求之一。旁边 其感觉症状，慢性疼痛的特点是损害认知任务，如注意力和 工作记忆，这取决于内侧前额叶皮层（mPFC）的胆碱能调制。因此，委员会认为， 发现mPFC失活对神经病理性疼痛表型有因果作用，我们的初步研究表明， 数据显示在雄性大鼠的mPFC锥体神经元中兴奋性胆碱能调节严重受损。 然而，介导mPFC失活的确切机制，这种失活如何影响疼痛， 感知和认知表现，以及它是否同样影响男性和女性， 未知我们的初步数据表明，由M1受体介导的电流对mPFC锥体细胞的增殖至关重要。 细胞兴奋性，并强烈降低神经性疼痛;我们的总体假设是，受损的 mPFC的胆碱能调节代表了神经病理性疼痛中mPFC失活的主要机制 并介导几种感觉、认知和情绪症状。特别是，我们假设， 神经病理性疼痛：（1）mPFC活性的胆碱能调节被破坏，这对神经病理性疼痛有重要作用。 两种性别中的整体mPFC失活;（2）阻断M1介导的mPFC兴奋足以模拟， 至少部分地，神经性疼痛表型;（3）抵消神经性疼痛表型的药理学操作。 胆碱能中断和恢复mPFC输出改善神经病性认知和感觉症状 痛苦为了验证这些假设，我们将利用神经病理性损伤的备用神经损伤（SNI）模型， 努力实现两个具体目标。在目标1中，我们将联合收割机结合单个胆碱能受体的光遗传学激活， 输入，急性切片中的膜片钳记录和PCR分析，以测试受损的假设， 胆碱能调节有助于整体mPFC失活，以确定受体的身份 参与，并剖析胆碱能输入的相对影响，从当地的中间神经元和从基底 前脑对mPFC活动的影响。在目标2中，我们将测试受损的 mPFC胆碱能调节。我们将使用体内化学遗传学和药理学调制的mPFC 逆转SNI表型我们获得的初步数据表明，通过增强mPFC兴奋性， 5 HT 1a受体的药理学拮抗作用具有有效的镇痛作用。相反，我们也将 研究在幼稚动物中阻断M1介导的mPFC兴奋是否足以模拟SNI 表型因此，我们的工作将为非阿片类神经性疼痛治疗确定新的潜在靶点。