Central glutamate signaling in postoperative pain regulation

 描述(由申请人提供)：术后疼痛是外科手术的主要并发症。迫切需要一种新的疗法，既能治疗感觉性和情感性疼痛症状，又能保持呼吸动力。然而，由于对疼痛在大脑中如何调节的理解存在根本差距，新型止痛药的开发受到了阻碍。这项建议的长期目标是了解术后疼痛的中枢调节。伏核(NAC)中的谷氨酸信号被认为是调节疼痛症状的信号。然而，在机制水平上，调节谷氨酸输入到NAC的来源还没有确定，NAC中靶向异恶唑丙酸(AMPA)受体治疗疼痛的能力也没有建立。此外，目前尚不清楚NAC中的谷氨酸信号是否是控制急性和慢性术后疼痛的常见机制。这项应用的总体目标是确定α-氨基-3-羟基-5-甲基-4-谷氨酸信号在前额叶皮质(PFC)到NAC的投射中的作用，以调节急慢性术后疼痛。中心假设是从PFC到NAC的谷氨酸输入可以减轻疼痛，而Ampakines可以增强NAC中的谷氨酸信号来治疗术后疼痛。这一假说得到了初步数据的支持，这些数据表明，PFC-NAC回路的光遗传激活可以抑制持续性疼痛，全身和NAC内注射Ampakines可以缓解慢性术后疼痛。在目的1中，我们将在两种大鼠模型上确定谷氨酸投射到NAC的镇痛作用：用于急性术后疼痛的爪状切开模型和用于术后持续性疼痛的备用神经损伤模型。利用初步实验中建立的技术，光敏通道视紫红质和卤视紫红质将分别用于光遗传激活和停用这种谷氨酸能投射。接下来，将使用标准疼痛行为分析来详细量化PFC-NAC回路的光遗传调制对感觉性和情感性疼痛症状的影响。在目标2中，将建立Ampakines的止痛效果和机制。已知Ampakines可以增加延髓中的谷氨酸信号，以治疗阿片类药物引起的低通气性。因此，临床上可用的Ampakines的止痛性能将在术后疼痛模型中作为单一药物和与阿片类药物联合使用来确定。下一步，将使用电生理记录来量化Ampakines增加NAC中AMPA受体电流的能力，行为测试将确定NAC中的AMPA受体专门介导Ampakines的止痛效果。这个项目具有创新性，因为它应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，因为它确定了PFC-NAC疼痛抑制回路是神经调节治疗的潜在靶点，更重要的是，它确立了Ampakines作为术后药物，可以治疗疼痛的感觉和情感症状，同时反对阿片类药物诱导的低通气性，为临床试验奠定了基础。

 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.