Mechanism of Gabapentin Analgesia

描述（由申请人提供）：摘要神经性疼痛反映了周围、脊髓、皮层下和皮层结构的无数变化。有趣的是，尽管发生了一系列令人困惑的变化，但许多批准的神经性疼痛治疗方法仍会增加、增强或模拟球脊髓抑制，包括吗啡、去甲肾上腺素（NA）再摄取抑制剂和可乐定。尽管临床研究表明神经性疼痛患者存在下降抑制的基线缺陷，但我们认为激活该通路是治疗的关键。GBP是一种安全有效的治疗神经性疼痛的常用药物。GBP镇痛依赖于与钙通道124亚基的相互作用，但GBP激活的镇痛回路尚不完全清楚。我们和其他人最近证明GBP在啮齿动物神经损伤和手术切口后激活球脊髓降去肾上腺素能通路。我们还证明口服GBP可显著增加慢性疼痛患者术后脑脊液NA浓度，减少阿片类药物需求。这些发现表明下行抑制的激活，而不是外周或脊柱作用，是GBP镇痛的关键。本提案的目标是确定英镑激活下降抑制的机制。由于下行抑制性去肾上腺素能轴突起源于脑干蓝斑核（LC）和邻近核，因此我们将LC作为GBP的作用靶点。首先，我们将利用LC中的免疫细胞化学和微透析方法来研究GBP激活NA神经元的局部机制，重点研究GABA和谷氨酸输入的作用。其次，我们将进行行为测试并测量脊髓背角微透析样品中的NA含量，以检查GBP在神经损伤后减少超敏反应和增加脊髓NA释放之间的联系，这是LC中NA神经元激活的结果。我们提出的研究不仅将为我们关于GBP镇痛的主要部位和作用机制的假设提供关键的检验，而且还将探索下行NA系统可用于治疗神经性疼痛的机制。

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.