Thalamo-Limbic Circuits in Pain

疼痛中的丘脑边缘回路

• 批准号: 10159317
• 负责人: Steve Davidson
• 金额: $ 35万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159317
• 关键词: Affective; Anatomy; Animal Model; Animals; Anterior; Anxiety; Area; Axon; Behavior; Behavioral; Biophysics; Brain; Cell Nucleus; Cells; Clinical; Cognitive; Cues; Data; Development; Dimensions; Electrophysiology (science); Emotional; Exhibits; Foundations; Future; G-Protein-Coupled Receptors; Genes; Goals; Human; In Vitro; Individual; Injury; Insula of Reil; Intervention; Intractable Pain; Knowledge; Lead; Learning; Measures; Membrane; Mental Depression; Metabotropic Glutamate Receptors; Modeling; Molecular Target; Morphology; Motivation; Mus; Neuroanatomy; Neurobiology; Neurons; Nociception; Outcome; Output; Pain; Pain Measurement; Pain Threshold; Pain management; Pain-Free; Pathway interactions; Patients; Persistent pain; Pharmacology; Physiological; Prosencephalon; Receptor Signaling; Regulation; Research; Rodent; Role; Sensory; Sensory Thresholds; Signal Transduction; Somatosensory Cortex; Spinal; Structure; Synapses; Synaptic plasticity; System; Techniques; Testing; Thalamic structure; Withdrawal; Work; behavioral pharmacology; chronic pain; chronic pain patient; cingulate cortex; clinical pain; coping; design and construction; experience; experimental study; hippocampal pyramidal neuron; improved; in vitro testing; in vivo; indexing; inflammatory pain; innovation; neural circuit; neurophysiology; neuroregulation; novel; optogenetics; pain behavior; pain model; pain processing; pain reduction; pain relief; painful neuropathy; patch clamp; postsynaptic; receptor; relating to nervous system; success; tool

Pain tolerance varies widely among peoples and, depending on external and internal circumstances, varies within an individual from moment to moment. Although the concept of pain tolerance is familiar, the neurobiological substrates that regulate pain tolerance are unknown. Pain tolerance requires motivational, emotional, and cognitive processing in addition to the sensory dimension of the pain experience. Achieving an understanding the specific neurons and circuits in the brain that regulate pain tolerance may to lead to breakthroughs that will enhance the capacity of patients to cope with intractable pain. This project utilizes innovative techniques to both assess pain tolerance behavior in animals, and to dissect the neural circuits thought to regulate pain tolerance. We have discovered that a subtype of pyramidal neuron in limbic cortical areas including the anterior cingulate cortex and insula becomes hyperexcitable during periods of lowered pain tolerance produced by injury. These neurons express GRM2, the gene encoding group II metabotropic glutamate receptors, which is a potential molecular target to control pain tolerance in clinical settings. The goals of this project are: 1) To identify the thalamo-limbic pathways that regulate pain tolerance; 2) To determine the role of GRM2 limbic cortical neurons in pain tolerance and nociceptive-withdrawal behaviors, and, 3) to determine whether pain tolerance can be modulated by pharmacological manipulation of group II metabotropic glutamate receptors. Optogenetic and pharmacological experiments will be performed in vivo in mouse to learn whether pain tolerance can be modulated independently of standard nociceptive-withdrawal thresholds. Modulation of neural activity in models of inflammatory and neuropathic pain will be tested to determine whether injury-induced changes to pain tolerance can be reversed. Neuro-anatomical and neurophysiological approaches in vitro will be used to generate new information on the plasticity of the thalamo-cortical circuits hypothesized to regulate pain tolerance and the membrane biophysics of GRM2 neurons. These experiments will be performed using animal models of persistent pain to determine whether function and anatomy of thalamo-cortical synapses and GRM2 neurons are altered by pain to provide mechanistic understanding for behavioral changes in pain tolerance. Pharmacological modulation of group II mGluR signaling will be tested in vitro to determine the potential for these receptors to be used in future clinical interventions. Completion of this project will generate new knowledge on the neural systems involved in the supraspinal processing of pain, including pain tolerance, and potentially catalyze an innovative shift in strategy for pain relief to enhance coping ability in chronic pain patients through neuromodulation.

不同民族之间的疼痛耐受性差异很大，并且根据外部和内部环境的不同，疼痛耐受性也不同 每时每刻都在一个人的内心。尽管疼痛耐受性的概念很熟悉， 调节疼痛耐受性的神经生物学底物尚不清楚。忍受疼痛需要动力， 除了疼痛体验的感官维度之外，还包括情绪和认知处理。实现 了解大脑中调节疼痛耐受性的特定神经元和回路可能会导致 突破将增强患者应对顽固性疼痛的能力。该项目利用 评估动物疼痛耐受行为并剖析神经回路的创新技术 被认为可以调节疼痛耐受性。我们发现边缘皮质中锥体神经元的一种亚型 在疼痛减轻期间，包括前扣带皮层和岛叶在内的区域变得过度兴奋 伤害产生的耐受性。这些神经元表达 GRM2，编码 II 组代谢型基因 谷氨酸受体，这是临床环境中控制疼痛耐受性的潜在分子靶点。这 该项目的目标是： 1）确定调节疼痛耐受性的丘脑边缘通路； 2) 至 确定 GRM2 边缘皮质神经元在疼痛耐受性和伤害性退缩行为中的作用， 3) 确定是否可以通过 II 组的药物操作来调节疼痛耐受性 代谢型谷氨酸受体。光遗传学和药理学实验将在体内进行 小鼠以了解是否可以独立于标准伤害性戒断来调节疼痛耐受性 阈值。将测试炎症和神经性疼痛模型中神经活动的调节 确定是否可以逆转损伤引起的疼痛耐受性变化。神经解剖学和 体外神经生理学方法将用于生成有关可塑性的新信息 丘脑皮质回路被认为调节疼痛耐受性和 GRM2 的膜生物物理学 神经元。这些实验将使用持续性疼痛的动物模型进行，以确定是否 丘脑皮质突触和 GRM2 神经元的功能和解剖结构会因疼痛而改变 对疼痛耐受性行为变化的机制理解。 II组的药理调节 mGluR 信号传导将在体外进行测试，以确定这些受体在未来临床中使用的潜力 干预措施。该项目的完成将产生有关神经系统的新知识 疼痛的脊髓上处理，包括疼痛耐受性，并有可能促进策略的创新转变 通过神经调节缓解疼痛，增强慢性疼痛患者的应对能力。