Central glutamate signaling in postoperative pain regulation

 描述（由申请人提供）：术后疼痛是手术的主要并发症。迫切需要治疗感觉和情感疼痛症状同时保留呼吸驱动的新疗法。然而，在理解疼痛如何在大脑中调节方面存在根本性的差距，阻碍了新型镇痛药的开发。这项建议的长期目标是了解术后疼痛的中枢调节。已知延髓核（NAc）中的谷氨酸信号传导调节疼痛症状。然而，在机制水平上，调节谷氨酸输入NAc的来源尚未确定，并且靶向NAc中谷氨酸的主要受体异恶唑丙酸（AMPA）受体以治疗疼痛的能力尚未建立。此外，尚不清楚NAc中的谷氨酸信号传导是否是控制急性和慢性术后疼痛的常见机制。本申请的总体目标是确定α-氨基-3-羟基-5-甲基-4-谷氨酸信号传导在从前额叶皮层（PFC）到NAc的投射中的作用，以调节急性和慢性术后疼痛。中心假设是从PFC到NAc的谷氨酸输入减少疼痛，并且AMPAkines可以增强NAc中的谷氨酸信号传导以治疗术后疼痛。该假设得到初步数据的支持，初步数据显示PFC-NAc回路的光遗传学激活抑制持续性疼痛，并且AMPAkine的全身和NAc内递送缓解慢性术后疼痛。在目标1中，将在两种大鼠模型中定义从PFC到NAc的谷氨酸投射的镇痛作用：急性术后疼痛的爪切口模型和持续性术后疼痛的备用神经损伤模型。光敏通道视紫红质和盐视紫红质将分别用于使用初步实验中建立的技术来光遗传学激活和失活该视紫红质能投射。接下来，将使用标准疼痛行为测定详细量化PFC-NAc回路的光遗传学调节对感觉和情感疼痛症状的影响。在目标2中，将建立AMPAkines的镇痛功效和机制。已知AMPakine增加髓质中的谷氨酸信号传导以治疗阿片样物质诱导的通气不足。因此，将在术后疼痛模型中确定临床上可用的AMPAkine作为单一药剂和与阿片类药物组合的疼痛缓解特性。接下来，将使用电生理学记录来量化AMPA激酶增加NAc中AMPA受体电流的能力，并且行为测试将确定NAc中的AMPA受体特异性介导AMPA激酶的镇痛作用。该项目具有创新性，因为它采用了一种新的系统神经科学方法来揭示一种新的中枢疼痛抑制机制。这项工作意义重大，因为它将PFC-NAc疼痛抑制回路确定为神经调节疗法的潜在靶点，更重要的是，它将AMPAkines确定为术后药物，可以治疗疼痛的感觉和情感症状，同时对抗阿片类药物诱导的通气不足，为临床试验奠定基础。

 DESCRIPTION (provided by applicant): Postoperative pain is a major morbidity of surgery. New therapies that treat both sensory and affective pain symptoms while preserving the respiratory drive are urgently needed. The development of novel analgesics is hindered, however, by a fundamental gap in understanding how pain is regulated in the brain. The long-term goal of this proposal is to understand the central regulation of postoperative pain. Glutamate signaling in the nucleus accumbens (NAc) is known to modulate pain symptoms. However, at the mechanistic level, the source of regulatory glutamate inputs to the NAc is not defined, and the ability to target isoxazolepropionic acid (AMPA) receptors, main receptors for glutamate, in the NAc to treat pain is not established. Furthermore, it is not known if glutamate signaling in the NAc is a common mechanism to control both acute and chronic postoperative pain. The overall objective of this application is to define the role of a-amino-3-hydroxy-5-methyl-4- glutamate signaling in the projection from the prefrontal cortex (PFC) to the NAc for the regulation of acute and chronic postoperative pain. The central hypothesis is that glutamate input from the PFC to the NAc decreases pain and that AMPAkines can enhance glutamate signaling in the NAc to treat postoperative pain. This hypothesis is supported by preliminary data showing that optogenetic activation of the PFC-NAc circuit inhibits persistent pain, and that systemic and intra-NAc delivery of AMPAkines relieves chronic postoperative pain. In Aim 1, the analgesic effect of the glutamate projection from the PFC to the NAc will be defined in two rat models: the paw incision model for acute postoperative pain and the spared nerve injury model for persistent postoperative pain. Light-sensitive channel rhodopsins and halorhodopsins will be used to optogenetically activate and deactivate this glutamatergic projection respectively, using techniques established in preliminary experiments. Next, the impact of optogenetic modulation of the PFC-NAc circuit on sensory and affective pain symptoms will be quantified in detail using standard pain behavior assays. In Aim 2, the analgesic efficacy and mechanism for AMPAkines will be established. AMPAkines are known to increase glutamate signaling in the medulla to treat opioid-induced hypoventilation. Thus, the pain-relieving property of clinically available AMPAkines will be determined, both as single agents and in combination with opioids, in postoperative pain models. Next, the ability of AMPAkines to increase AMPA receptor currents in the NAc will be quantified using electrophysiological recordings, and behavior tests will determine that AMPA receptors in the NAc specifically mediate the analgesic effects of AMPAkines. This project is innovative because it applies a new systems neuroscience approach to uncover a novel central pain-inhibitory mechanism. The work is significant because it identifies the PFC-NAc pain-inhibitory circuit as a potential target for neuromodulation therapies and, more importantly, it establishes AMPAkines as postoperative drugs that can treat both sensory and affective symptoms of pain while opposing opioid-induced hypoventilation, laying the groundwork for clinical trials.