Reversal of pain by group II metabotropic glutamate receptors

II 类代谢型谷氨酸受体逆转疼痛

基本信息

批准号：
8255236
负责人：
Steve Davidson
金额：
$ 5.13万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8255236
关键词：
Action Potentials Adverse effects Antibody Specificity Bathing Behavior Behavioral Binding Binding Sites Biological Assay Calcium Chemosensitization Data Development Esthesia Functional disorder Glutamates Goals Human Hyperalgesia Hypersensitivity Immunohistochemistry Individual Inflammation Inflammation Mediators Inflammatory Injury Ion Channel Knockout Mice Maintenance Measures Mediating Membrane Metabotropic Glutamate Receptors Methods Modeling Molecular Mus Neurobiology Neurons Neuropathy Nociception Nociceptors Operant Conditioning Pain Pain management Patch-Clamp Techniques Peripheral Pharmaceutical Preparations Play Prevalence Recovery Research Resistance Resolution Role Signal Transduction Sodium Spinal Ganglia TRPV1 gene Testing Tetrodotoxin Time Whole Organism Work aging population base behavior test chronic pain design inflammatory neuropathic pain inflammatory pain medical attention metabotropic glutamate receptor 2 metabotropic glutamate receptor 3 neuronal excitability neurophysiology neurotransmission novel painful neuropathy patch clamp public health relevance receptor research study voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Inflammation or injury can sensitize nociceptive neurons and the resulting hyperexcitability is thought to mediate increased pain sensation. Although pain typically resolves with time, the mechanisms that promote the return to Dr. g are poorly understood. Dysfunction of such a mechanism could contribute to the persistence of chronic pain, while activation could provide relief from pain. The central hypothesis of this proposal is that peripheral group II metabotropic glutamate receptors (mGluRs) regulate the reversal of nociceptor sensitization and hyperalgesia. This hypothesis will be tested with a combination of anatomical, neurophysiological, and behavioral methods. Two subtypes of group II mGluRs exist, mGluR2 and mGluR3. The specific expression of each subtype within dorsal root ganglia (DRG) will be characterized. We will then determine whether mGluR2 or mGluR3 is necessary for the normal recovery from inflammatory and neuropathic pain using mGluR2 and mGluR3 knockout mice. We propose that group II mGluRs can reverse nociceptor sensitization. To test this, patch-clamp techniques will be used to measure neuronal excitability in sensitized DRG neurons. After pharmacological manipulation of group II mGluRs excitability will be reassessed. Membrane excitability is determined by current flux through ion channels, but it is not clear whether group II mGluRs regulate currents involved in sensitization. Two candidate currents, the tetrodotoxin- resistant Na+ and T-type Ca2+ current will be tested for their ability to be modulated by group II mGluRs in sensitized DRG neurons. We hypothesize that group II mGluRs are involved in the endogenous recovery from hyperalgesia. To test this, we will determine whether positive allosteric modulators of group II mGluRs accelerate the recovery from inflammatory hyperalgesia. Finally, we will determine whether group II mGluRs are capable of relieving ongoing neuropathic pain using an operant conditioning paradigm.

描述（由申请人提供）：炎症或损伤可以使伤害性神经元敏感，而导致的过度兴奋性被认为可以介导增加的疼痛感觉。尽管疼痛通常会随着时间的流逝而解决，但促进G博士返回G博士的机制知之甚少。这种机制的功能障碍可能导致慢性疼痛的持久性，而激活可以缓解疼痛。该提议的中心假设是外围II组代谢型谷氨酸受体（MGLURS）调节了伤害感受器敏感性和超痛性的逆转。该假设将通过解剖学，神经生理和行为方法的结合进行检验。存在MGLUR2和MGLUR3的II组Mglurs的两个亚型。将表征背部根神经节（DRG）内每种亚型的特定表达。然后，我们将确定使用MGLUR2和MGLUR3敲除小鼠从炎症和神经性疼痛中恢复正常的MGLUR2或MGLUR3是否需要。我们提出，II组MGLUR可以逆转伤害感受器的敏化。为了测试这一点，斑块钳技术将用于测量敏化DRG神经元中的神经元兴奋性。在对II组MGLURS的药理操作后，将重新评估兴奋性。膜兴奋性取决于通过离子通道的电流通量确定，但是尚不清楚II组MGLURS是否调节参与敏化的电流。两种候选电流，抗二毒素 - 耐药Na+和T型Ca2+电流，将测试其在敏化的DRG神经元中由II组MGLURS调节的能力。我们假设II组MGLUR参与了从痛觉过敏中的内源性恢复。为了测试这一点，我们将确定II组MGLURS的阳性变构调节剂是否会加速炎症性痛觉过敏的恢复。最后，我们将确定II组MGLUR是否能够使用操作调节范式来缓解持续的神经性疼痛。