Reversal of pain by group II metabotropic glutamate receptors

II 类代谢型谷氨酸受体逆转疼痛

• 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
• 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

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变得敏感，并且由此产生的过度兴奋被认为会介导疼痛感的增加。虽然疼痛通常会随着时间的推移而消失，但促进回归 g 博士的机制却知之甚少。这种机制的功能障碍可能会导致慢性疼痛的持续存在，而激活则可以缓解疼痛。该提议的中心假设是外周 II 族代谢型谷氨酸受体 (mGluR) 调节伤害感受器敏化和痛觉过敏的逆转。这一假设将通过解剖学、神经生理学和行为学方法的结合来检验。 II 组 mGluR 存在两种亚型：mGluR2 和 mGluR3。将表征背根神经节（DRG）内每种亚型的具体表达。然后，我们将使用 mGluR2 和 mGluR3 敲除小鼠来确定 mGluR2 或 mGluR3 对于炎症和神经性疼痛的正常恢复是否是必需的。我们认为 II 类 mGluR 可以逆转伤害感受器敏化。为了测试这一点，将使用膜片钳技术来测量敏感的 DRG 神经元的神经元兴奋性。对 II 组 mGluR 进行药理学操作后，将重新评估兴奋性。膜兴奋性由通过离子通道的电流通量决定，但尚不清楚 II 族 mGluR 是否调节参与敏化的电流。将测试两种候选电流（河豚毒素抗性 Na+ 电流和 T 型 Ca2+ 电流）在敏化 DRG 神经元中受 II 组 mGluR 调节的能力。我们假设 II 组 mGluR 参与痛觉过敏的内源性恢复。为了测试这一点，我们将确定 II 组 mGluR 的正变构调节剂是否加速炎症性痛觉过敏的恢复。最后，我们将确定 II 组 mGluR 是否能够使用操作性条件反射范式缓解持续的神经性疼痛。