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MECHANISMS UNDERLYING INTRACELLULAR MGLUR5 ROLE IN NOCICEPTION

细胞内 MGLUR5 在伤害伤害中的作用机制

基本信息

批准号：
8584220
负责人：
KAREN L O'MALLEY
金额：
$ 19万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8584220
关键词：
Acute Pain Address Adverse effects Affect Agonist Analgesics Anti-Inflammatory Agents Anti-inflammatory Behavioral Biochemical Cell membrane Cell surface Cells Chronic Chronic inflammatory pain Clinical Data Development Dose Dose-Limiting Drug Targeting Economic Burden Future G-Protein-Coupled Receptors GRM5 gene Glutamate Transporter Glutamates Goals Health Care Visit Inflammation Injury Institute of Medicine (U.S.)Intracellular Membranes Knockout Mice Lead Ligands MAPK3 gene Maintenance Metabotropic Glutamate Receptors Mitogen-Activated Protein Kinases Modeling Molecular Nervous system structure Neurons Neuropathy Neurotransmitters Nociception Nuclear Nuclear Envelope Opiates Pain Pain management Peripheral Persistent pain Pharmaceutical Preparations Pharmacologic Substance Phosphorylation Play Population Posterior Horn Cells Productivity Publications Rattus Role Series Signal Pathway Signal Transduction Societies Sodium Spinal Spinal Cord System TRPV1 gene Techniques Therapeutic central sensitization chronic pain cost drug discovery fenobam improved in vivo inflammatory pain novel novel therapeutics painful neuropathy prevent public health relevance receptor response sensor tool

项目摘要

DESCRIPTION (provided by applicant): It is estimated that almost 30% of people in the US endure chronic pain. While certain drugs can control some types of pain, many have limitations as well as dose-limiting side effects. Thus safer, more specific drugs would have high clinical utility. Recent studies have shown that the metabotropic glutamate receptor, mGluR5, plays a role in the development and maintenance of chronic pain such that pharmacological antagonism of mGluR5 is thought to be analgesic. Intriguingly, mGluR5, not only plays a critical role on the plasma membrane but also an unknown but profound role on nuclear membranes of the spinal cord neurons that are associated with chronic inflammatory pain. For example, increased levels of mGluR5 are found on nuclear membranes of spinal cord dorsal horn neurons in rats with neuropathic pain. To date the specific role of intracellular mGluR5 has been completely overlooked in any neuronal type including dorsal horn neurons, despite studies showing 60-90% of the receptor is on intracellular membranes. Thus a clearer understanding of the specific role played by spinal intracellular mGluR5 in chronic inflammatory pain could provide a strong rationale for the development of restricted antagonists as novel pain therapeutics. It is therefore the goal of this proposal to examine the role of spinal intracellular mGluR5 in chronic inflammatory pain. Specifically we hypothesize that intracellular mGluR5 plays an important role in modulating chronic pain models. Using pharmacological, biochemical, and molecular techniques, we address the following questions: Does blockade of cell surface mGluR5 with an impermeable antagonist (LY393053) prevent downstream sequelae of glutamate induced inflammation or neuropathic injury; and 2) what are the underlying signaling mechanisms associated with intracellular mGluR5-dependent chronic inflammatory pain. These studies will reveal the cellular and molecular mechanisms by which mGluR5 modulates chronic pain, and will clearly define the role of intracellular receptors in an in vivo setting. Subsequent studies wll assess downstream targets altered by mGluR5 signaling. Inasmuch as mGluR5 is involved in both peripheral and central sensitization it represents an attractive target for drug discovery. Future studies targeting drugs to cell surface versus intracellular receptors might lead to new therapeutic tools for chronic inflammatory pain.

描述（由申请人提供）：据估计，美国近30%的人患有慢性疼痛。虽然某些药物可以控制某些类型的疼痛，但许多药物都有局限性以及剂量限制的副作用。因此，更安全、更特异的药物将具有很高的临床效用。最近的研究表明，代谢性谷氨酸受体mGluR5在慢性疼痛的发生和维持中起作用，因此mGluR5的药理拮抗作用被认为是镇痛的。有趣的是，mGluR5不仅在质膜上起关键作用，而且在与慢性炎症性疼痛相关的脊髓神经元核膜上也起着未知但深刻的作用。例如，在神经性疼痛大鼠脊髓背角神经元核膜上发现mGluR5水平升高。迄今为止，细胞内mGluR5的特定作用在包括背角神经元在内的任何神经元类型中都被完全忽视，尽管研究表明60-90%的受体位于细胞膜上。因此，更清楚地了解脊髓细胞内mGluR5在慢性炎症性疼痛中的具体作用，可以为开发限制性拮抗剂作为新型疼痛治疗药物提供强有力的理论依据。因此