MECHANISMS UNDERLYING INTRACELLULAR MGLUR5 ROLE IN NOCICEPTION

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，但许多药物具有局限性和剂量限制性副作用。因此，更安全、更特异的药物将具有更高的临床实用性。最近的研究表明，代谢型谷氨酸受体mGluR 5在慢性疼痛的发展和维持中起作用，因此认为mGluR 5的药理学拮抗作用是镇痛的。有趣的是，mGluR 5不仅在质膜上起着关键作用，而且在与慢性炎性疼痛相关的脊髓神经元的核膜上也起着未知但深远的作用。例如，在患有神经性疼痛的大鼠中，在脊髓背角神经元的核膜上发现mGluR 5水平增加。迄今为止，细胞内mGluR 5的特定作用在任何神经元类型（包括背角神经元）中已被完全忽视，尽管研究显示60-90%的受体位于细胞内膜上。因此，更清楚地了解脊髓细胞内mGluR 5在慢性炎性疼痛中发挥的特定作用，可以为开发限制性拮抗剂作为新型疼痛治疗剂提供强有力的理论基础。因此 该提案的目的是研究脊髓细胞内mGluR 5在慢性炎性疼痛中的作用。具体而言，我们假设细胞内mGluR 5在调节慢性疼痛模型中起着重要作用。使用药理学，生物化学和分子技术，我们解决了以下问题：阻断细胞表面mGluR 5与不可渗透的拮抗剂（LY 393053）防止下游后遗症谷氨酸诱导的炎症或神经性损伤;和2）什么是潜在的信号转导机制与细胞内mGluR 5依赖性慢性炎性疼痛。这些研究将揭示mGluR 5调节慢性疼痛的细胞和分子机制，并将明确定义细胞内受体在体内环境中的作用。后续研究将评估mGluR 5信号转导改变的下游靶点。由于mGluR 5参与外周和中枢致敏，因此它代表了药物发现的有吸引力的靶标。未来的研究将药物靶向细胞表面与细胞内受体，可能会导致新的慢性炎症性疼痛的治疗工具。

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.