Thalamo-Limbic Circuits in Pain

不同民族的疼痛耐受性差异很大，而且取决于外部和内部环境，也会有所不同 在一个人的内心里，每时每刻。虽然疼痛耐受性的概念很熟悉，但 调节疼痛耐受性的神经生物学底物尚不清楚。疼痛的耐受需要有动力， 除了疼痛体验的感官维度外，还有情感和认知处理。实现 了解大脑中调节疼痛耐受性的特定神经元和电路可能会导致 将提高患者应对顽固性疼痛的能力的突破。这个项目利用了 评估动物的疼痛耐受行为和解剖神经回路的创新技术 被认为可以调节疼痛耐受性。我们发现边缘皮质锥体神经元的一种亚型 包括前扣带回皮质和脑岛在内的区域在疼痛减轻时变得高度兴奋。 因受伤而产生的耐受性。这些神经元表达GRM2，编码II组代谢性基因 谷氨酸受体，这是一个潜在的分子靶点，在临床环境中控制疼痛耐受。这个 这个项目的目标是：1)确定调节疼痛耐受性的丘脑-边缘通路；2) 确定GRM2边缘皮质神经元在疼痛耐受和伤害性戒断行为中的作用， 以及，3)确定II组的药物操作是否可以调节疼痛耐受性 代谢性谷氨酸受体。光遗传学和药理学实验将于#年在体内进行。 小鼠学习疼痛耐受性是否可以独立于标准的伤害性戒断而调节 阈值。炎症性疼痛和神经病理性疼痛模型中神经活动的调节将被测试 确定损伤引起的疼痛耐受性变化是否可以逆转。神经解剖学和 体外神经生理学方法将被用来产生关于细胞可塑性的新信息 丘脑-皮质环路假想调节疼痛耐受性和GRM2的膜生物物理 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 疼痛改变了丘脑皮质突触和GRM2神经元的功能和解剖，以提供 对疼痛耐受性行为变化的机械论理解。II组的药理调节作用 MGluR信号将在体外进行测试，以确定这些受体在未来临床应用的潜力 干预措施。这个项目的完成将产生关于 脊椎上对疼痛的处理，包括疼痛耐受性，并可能催化战略的创新转变 用于缓解疼痛，通过神经调节提高慢性疼痛患者的应对能力。

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.