Hemichannels, astrocytic release, and neuropathic pain

半通道、星形胶质细胞释放和神经性疼痛

• 批准号: 8909101
• 负责人: RU-RONG JI
• 金额: $ 38.81万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8909101
• 关键词: Acute Pain; Address; American; Astrocytes; Behavioral; Bioluminescence; Communication; Connexin 43; Development; Electrophysiology (science); Functional disorder; Gap Junctions; Glutamates; Health; Homeostasis; Image; Injection of therapeutic agent; Injury; Lead; Ligation; Long-Term Potentiation; MAPK14 gene; Maintenance; Measures; Mediating; Medical; Microglia; Morbidity - disease rate; Movement; Mus; Nerve; Neuroglia; Neuronal Plasticity; Neurons; Pain; Pain management; Paracrine Communication; Pathogenesis; Pathway interactions; Patients; Peripheral nerve injury; Play; Process; Quality of life; Role; Route; Scientist; Slice; Source; Spinal; Spinal Cord; Spinal cord injury; Spinal nerve structure; Stroke; Synapses; Synaptic plasticity; Tamoxifen; Testing; Therapeutic; Time; Transgenic Mice; Trauma; Work; base; behavior test; cell motility; cell type; chronic neuropathic pain; chronic pain; gain of function; in vivo; in vivo imaging; innovation; interdisciplinary approach; loss of function; mouse model; nerve injury; painful neuropathy; patch clamp; preference; prevent; promoter; receptor; response; spontaneous pain; two-photon

DESCRIPTION (provided by applicant): Pain conditions are a major health problem in the US and lead to medical morbidity and a reduced quality of life for millions of Americans. Chronic neuropathic pain conditions are especially difficult to treat. A largely unaddressed challenge is how the transition from acute pain to chronic neuropathic pain occurs and how to prevent and reverse this transition in patients. Spinal cord synaptic plasticity and long-term potentiation (LTP) have been strongly implicated in chronic neuropathic pain development. Accumulating evidence also points to an important role of glial cells in the pathogenesis of neuropathic pain. Astrocytes are the most abundant cell type in the CNS and maintain the homeostasis of the CNS. It is well established that astrocytic hemichannels such as connexin-43 (Cx43) constitute an important pathway for gliotransmitter release. Although Cx43 was typically thought to regulate gap junction communication between astrocytes, this function could be switched to paracrine signaling via ATP and glutamate release under injury conditions. Our central hypothesis is hemichannels-mediated gliotransmitter release after nerve injury contributes to transition from acute pain to chronic neuropathic pain by modulating spinal cord synaptic plasticity and LTP. We will test our central hypothesis by addressing the following 4 specific aims: Aim 1 will test the hypothesis that spinal nerve injury increases glutamate and ATP release from spinal cord astrocytes; Aim 2 will test the hypothesis that Cx43-mediated astrocytic ATP release plays a chief role in microglia activation and microgliosis in the spinal cord after spinal nerve injury; Aim 3 will determine the role of Cx43-medicated astrocytic gliotransmitter release in spinal cord synaptic plasticity and LTP after nerve injury; Aim 4 will define the role o astrocytic Cx43 in neuropathic pain development and maintenance after nerve injury. This proposal will involve formation of an innovative partnership between Dr. Ji, a pain scientist with expertise in studying neuronal-glial interactions and neural plasticity in neuropathic pain, and Dr Nedergaard with expertise in studying astrocytic ATP and glutamate release after spinal cord injury and stroke. This application will employ a multidisciplinary approach including the use of inducible transgenic mice with genetically modified astrocytes, in vivo imaging of ATP release (bioluminescence) and microglia motility and Ca2+ changes (2-photon) in the spinal cord, behavioral testing of evoked and ongoing neuropathic pain after nerve injury, and ex vivo and in vivo electrophysiology in the spinal cord. The proposed studies will provide a step-by-step analysis of neuron- glia interactions initiated by nerve injury and may comprise an efficient means to prevent and treat chronic pain.

描述（由申请人提供）：疼痛状况是美国的主要健康问题，导致医疗发病率和数百万美国人的生活质量降低。慢性神经性疼痛状况特别困难。一个在很大程度上没有解决的挑战是如何发生从急性疼痛到慢性神经性疼痛的过渡以及如何预防和扭转患者的过渡。脊髓突触可塑性和长期增强（LTP）与慢性神经性疼痛发育有关。积累证据也表明神经胶质细胞在神经性疼痛的发病机理中的重要作用。星形胶质细胞是中枢神经系统中最丰富的细胞类型，并保持中枢神经系统的稳态。众所周知，星形胶质细胞半通道（例如连接蛋白43（CX43））构成了胶质递升释放的重要途径。尽管通常认为CX43调节星形胶质细胞之间的间隙连接通信，但在损伤条件下，该功能可以通过ATP和谷氨酸释放转换为旁分泌信号传导。我们的中心假设是通过调节脊髓突触可塑性和LTP调节神经损伤后半通道介导的神经透明释放释放的神经透明释放。我们将通过解决以下4个特定目的来检验中心假设：AIM 1将检验以下假设：脊髓神经损伤会增加脊髓星形胶质细胞的谷氨酸和ATP释放。 AIM 2将检验以下假设：CX43介导的星形细胞ATP释放在脊髓神经损伤后的小胶质细胞激活和小胶质细胞症中起主要作用。 AIM 3将确定CX43药物的星形胶质神经胶糖在神经损伤后的脊髓突触可塑性和LTP中的作用； AIM 4将定义o星形细胞CX43在神经损伤后神经性疼痛发育和维持中的作用。该提案将涉及在研究神经性疼痛中具有专业知识的痛苦科学家JI博士之间建立创新的伙伴关系，而神经性疼痛中的神经可塑性和Nedergaard博士在研究星形胶质细胞ATP和脊髓损伤和Stroke后释放的星形胶质细胞ATP和glutamate释放方面具有专业知识。 This application will employ a multidisciplinary approach including the use of inducible transgenic mice with genetically modified astrocytes, in vivo imaging of ATP release (bioluminescence) and microglia motility and Ca2+ changes (2-photon) in the spinal cord, behavioral testing of evoked and ongoing neuropathic pain after nerve injury, and ex vivo and in vivo electrophysiology in the spinal 绳索。拟议的研究将对通过神经损伤引发的神经元相互作用提供分步分析，并可能包括预防和治疗慢性疼痛的有效手段。