Mechanism of Gabapentin Analgesia

描述（由申请人提供）：摘要神经性疼痛反映了外周、脊髓、皮质下和皮质结构的无数变化。有趣的是，尽管这种令人困惑的变化，许多批准的治疗神经性疼痛招募，增强，或模拟球脊髓抑制，包括吗啡，去甲肾上腺素（NA）再摄取抑制剂，可乐定。尽管临床研究表明神经病理性疼痛患者存在下行抑制的基线缺陷，但我们认为激活这一通路是治疗的关键。GBP（GBP）通常用作神经性疼痛的安全有效的治疗。GBP镇痛依赖于与钙通道124亚基的相互作用，但GBP激活镇痛的回路并不完全清楚。我们和其他人最近证明，GBP激活神经损伤后和手术切口后的啮齿动物的下降球脊髓去甲肾上腺素能通路。我们还表明，口服GBP显着增加脑脊液中的NA浓度，并减少慢性疼痛患者手术后阿片类药物的需求。这些研究结果表明，下行抑制的激活，而不是外周或脊髓的行动，是关键的GBP镇痛。这个提议的目的是确定GBP激活下行抑制的机制。由于下行抑制性去甲肾上腺素能轴突起源于蓝斑（LC）和邻近的核团在脑干，我们专注于LC作为GBP的作用靶点。首先，我们将利用免疫细胞化学和微透析方法在LC检查GBP激活NA神经元的本地机制，重点是GABA和谷氨酸输入的作用。其次，我们将进行行为测试和测量NA含量的微透析样品从脊髓背角检查GBP的行动之间的联系，以减少神经损伤后的超敏反应和增加脊髓NA释放，作为一个结果，激活NA神经元在LC。拟议的研究将不仅提供关键的测试，我们的假设，这个主要网站和GBP的镇痛作用机制，但也探针机制，其中下行NA系统可以招募治疗神经病理性疼痛。 公共卫生相关性：加巴喷丁被广泛用于治疗慢性疼痛，但其作用机制尚不清楚。我们最近发现，加巴喷丁激活了一种天然的疼痛缓解机制，在这项提案中，我们将研究加巴喷丁如何刺激人体自身的疼痛缓解系统在慢性疼痛中发挥作用。

DESCRIPTION (provided by applicant): Abstract Neuropathic pain reflects a myriad of changes in the periphery, spinal cord, and subcortical and cortical structures. Interestingly, despite this baffling array of changes, many approved treatments for neuropathic pain recruit, augment, or mimic bulbospinal inhibition including morphine, noradrenaline (NA) re-uptake inhibitors, and clonidine. Although clinical studies suggest a baseline deficit of descending inhibition in patients with neuropathic pain, we believe that activation of this pathway is key to its treatment. GBP (GBP) is commonly used as a safe and effective treatment of neuropathic pain. GBP analgesia depends on an interaction with the 124 subunit of calcium channels, but the circuits activated by GBP for analgesia are not entirely known. We and others recently demonstrated that GBP activates the descending bulbospinal noradrenergic pathway after nerve injury and after surgical incision in rodents. We also demonstrated that orally administered GBP significantly increases NA concentration in cerebrospinal fluid and decreases opioid requirements after surgery in patients with chronic pain. These findings argue that activation of descending inhibition, rather than peripheral or spinal actions, is pivotal for GBP analgesia. The goals of this proposal are to identify the mechanisms by which GBP activates descending inhibition. Since descending inhibitory noradrenergic axons originate from the locus coeruleus (LC) and adjacent nuclei in the brainstem, we focus on the LC as a target of action of GBP. Initially, we will utilize immunocytochemistry and microdialysis methods in LC to examine the local mechanisms by which GBP activates NA neurons, focusing on the roles of GABA and glutamate inputs. Secondly, we will perform behavioral tests and measure NA content in microdialysis samples from spinal dorsal horn to examine the link between actions of GBP to reduce hypersensitivity after nerve injury and to increase spinal NA release, as a consequence of activation of NA neurons in LC. The proposed studies will not only provide critical tests of our hypothesis of this primary site and mechanism of action of GBP for analgesia but also probe mechanisms by which the descending NA system can be recruited to treat neuropathic pain. PUBLIC HEALTH RELEVANCE: Gabapentin is widely used to treat chronic pain, but how it works is not well understood. We recently found that gabapentin activates a natural pain-relief mechanism, and in this proposal, we will study how gabapentin stimulates the body's own pain relieving system to work in chronic pain.