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Central glia/cytokines and descending facilitation in orofacial neuropathic pain

口面部神经病理性疼痛的中枢神经胶质细胞/细胞因子和下降促进

基本信息

批准号：
8070372
负责人：
Feng Wei
金额：
$ 35.62万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8070372
关键词：
Affect Animal Model Animals Anticonvulsants Antidepressive Agents Attenuated Behavioral Biological Brain Stem Cells Chimeric Proteins Chronic Clinical Clinical Data Cognitive Cytokine Activation Cytokine Receptors Data Dependence Development Event Fiber Glutamate Receptor Glutamates Hyperalgesia Immunohistochemistry Inflammatory Injury Interleukin-1 Interleukin-1 Receptors Interleukins Isoxazoles Link Maintenance Measurement Measures Mechanics Mediator of activation protein Metabolic Methods Microinjections Minocycline Modeling Molecular Motor N-Methyl-D-Aspartate Receptors Nerve Neuroglia Neuronal Plasticity Neurons Nociception Orofacial Pain Output Pain Pathway interactions Patients Peripheral Peripheral nerve injury Persistent pain Pharmaceutical Preparations Phosphorylation Play Process Propionates Rattus Recombinants Refractory Role Sensory Series Signal Pathway Signal Transduction Spinal Spinal Cord Spinal nerve structure Structure Symptoms Synapses Syndrome TNF gene TNFRSF1A gene Techniques Testing Time Tissues Trauma Trigeminal Neuralgia Trigeminal System Trigeminal nerve structure Tumor Necrosis Factor-alpha Western Blotting active control afferent nerve allodynia chemical release chronic constriction injury chronic pain constriction cytokine dental surgery design dorsal horn fluorocitrate human subject inflammatory pain inhibitor/antagonist injured maxillary nerve mechanical allodynia nerve injury neurochemistry neuromechanism novel novel therapeutic intervention orofacial painful neuropathy receptor research study sciatic nerve transmission process

项目摘要

DESCRIPTION (provided by applicant): The clinical orofacial pain syndromes are believed to be frequently related to trigeminal nerve damage as a result of trauma or dental surgery and offer a most difficult challenge to therapy. Trigeminal neuropathic pain occurs more frequently than that at spinal levels, but most animal studies on neuropathic pain describe data from animal models of spinal nerve injuries. Thus, in order to clarify the mechanisms underlying trigeminal neuropathic pain, animal models have to be created specifically for the trigeminal system. Evidence has emerged that the maintenance of neuropathic pain depends on descending facilitation from the rostral ventromedial medulla (RVM), a pivotal structure in descending pain modulation. Recent studies suggest that activated glial cells and released proinflammatory cytokines are intimately involved in spinal sensitization after nerve injury. However, a potential contribution of glial-neuronal interactions in the RVM to the development of neuropathic pain has not been studied. We propose to modify a rat model of chronic constriction injury of the infraorbital nerve (CCI-ION) with a new nocifensive measurement and study novel mechanisms underlying descending facilitation of trigeminal neuropathic pain with an emphasis on glial-neuronal interactions in the RVM. Our major hypotheses are that 1) nerve injury induces neuronal plasticity in the RVM through activation of glial and glutamate receptors and related signaling pathways and 2) glial activation and cytokine release affect or facilitate neuronal plasticity through interactions with neuronal glutamate receptors and play a critical role in the development of neuropathic pain. Aim 1 will set up a reliable method to measure mechanical hyperalgesia and allodynia in the CCI-ION model and to test the hypothesis that glial cells are activated and proinflammatory cytokines are upregulated in the RVM after nerve injury. Aim 2 will test the hypothesis that the receptors of these cytokines are expressed in RVM neurons and upregulated in the RVM after CCI-ION. Aim 3 will test the hypothesis that the inhibition of glial function and blockade of cytokine action in the RVM attenuate allodynia associated with CCI-ION. Aim 4 will test the hypothesis that glial activation and concomitant cytokine release are involved in neural plasticity in the RVM through interactions with neuronal glutamate receptors, and play a critical role in descending facilitation of neuropathic pain. The studies will advance our understanding of the mechanisms of orofacial neuropathic pain and facilitate the design of new therapeutic approaches.

描述（由申请人提供）：临床口面疼痛综合征被认为经常与创伤或牙科手术导致的三叉神经损伤有关，并对治疗提出了最困难的挑战。三叉神经性疼痛比脊髓水平更频繁地发生，但大多数关于神经性疼痛的动物研究描述了来自脊神经损伤动物模型的数据。因此，为了阐明三叉神经病理性疼痛的机制，必须建立专门针对三叉神经系统的动物模型。有证据表明，神经病理性疼痛的维持依赖于延髓头端腹内侧（RVM）的下行易化，这是下行疼痛调制的关键结构。最近的研究表明，激活的胶质细胞和释放的促炎细胞因子密切参与神经损伤后的脊髓敏化。然而，尚未研究RVM中神经胶质-神经元相互作用对神经病理性疼痛发展的潜在贡献。我们建议修改一个大鼠模型的慢性压迫性损伤的眶下神经（CCI-ION）与一个新的nocifensive测量和研究新的机制的基础上下行促进三叉神经病理性疼痛的RVM中的神经胶质细胞-神经元的相互作用的重点。我们的主要假设是：1）神经损伤通过激活胶质细胞和谷氨酸受体及相关信号通路诱导RVM中的神经元可塑性; 2）胶质细胞活化和细胞因子释放通过与神经元谷氨酸受体相互作用影响或促进神经元可塑性，并在神经病理性疼痛的发展中发挥关键作用。目的1将建立一种可靠的方法来测量机械性痛觉过敏和异常性疼痛的CCI-ION模型，并测试神经损伤后RVM中胶质细胞被激活和促炎细胞因子上调的假设。目的2将验证这一假设，即这些细胞因子的受体在RVM神经元中表达，并在CCI-ION后在RVM中上调。目的3将检验RVM中胶质细胞功能的抑制和细胞因子作用的阻断减轻与CCI-ION相关的异常性疼痛的假设。目的4将测试的假设，胶质细胞激活和伴随的细胞因子释放参与神经可塑性的RVM通过与神经元谷氨酸受体的相互作用，并在下行促进神经病理性疼痛中发挥关键作用。这些研究将促进我们对口面神经病理性疼痛机制的理解，并促进新的治疗方法的设计。