Mechanism of Gabapentin Analgesia

加巴喷丁镇痛机制

• 批准号: 7574453
• 负责人: Kenichiro Hayashida
• 金额: $ 7.4万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7574453
• 关键词: Absence of pain sensation; Analgesics; Axon; Brain Stem; Calcium Channel; Cell Nucleus; Cerebrospinal Fluid; Clinical Research; Clonidine; Development; Glutamates; Goals; Hypersensitivity; Laboratories; Link; Measures; Methods; Microdialysis; Modeling; Morphine; Neurons; Norepinephrine; Operative Surgical Procedures; Opioid; Pain; Pathway interactions; Patients; Peripheral; Peripheral nerve injury; Pharmaceutical Preparations; Preparation; Rattus; Recruitment Activity; Rodent; Role; Sampling; Site; Slice; Spinal; Spinal Cord; Structure; Surgical incisions; System; Testing; Work; abstracting; behavior test; chronic pain; dorsal horn; effective therapy; gabapentin; gamma-Aminobutyric Acid; immunocytochemistry; inhibitor/antagonist; locus ceruleus structure; nerve injury; noradrenergic; painful neuropathy; public health relevance; uptake

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.

描述(申请人提供)：摘要神经病理性疼痛反映了外周、脊髓、皮质下和皮质结构的无数变化。有趣的是，尽管有这样一系列令人费解的变化，许多被批准的神经病理性疼痛的治疗方法包括吗啡、去甲肾上腺素(NA)再摄取抑制剂和可乐定，它们重新招募、增强或模拟了球脊髓抑制。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，但我们认为这一通路的激活是其治疗的关键。银杏叶提取物(GBP)是治疗神经病理性疼痛的一种安全有效的方法。GBP的镇痛作用依赖于与钙通道124亚单位的相互作用，但GBP激活的镇痛回路尚不完全清楚。我们和其他人最近证实，在啮齿动物的神经损伤和手术切开后，GBP激活球脊髓去甲肾上腺素能下行通路。我们还证明，口服GBP显著增加了慢性疼痛患者手术后脑脊液中NA的浓度，减少了阿片类药物的需求。这些发现表明，下行抑制的激活，而不是外周或脊髓活动，是GBP镇痛的关键。该提案的目的是确定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脑干蓝斑(LC)和邻近的核团，因此我们将重点放在蓝斑作为GBP的作用靶点。首先，我们将在LC中利用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，重点是GABA和谷氨酸输入的作用。其次，我们将进行行为学测试和测量脊髓背角微透析样本中NA的含量，以检验GBP降低神经损伤后的过敏性和增加脊髓NA释放之间的联系，这是LC内NA神经元激活的结果。这些研究不仅将对我们关于GBP用于镇痛的主要部位和作用机制的假说提供关键的检验，而且还将探索下行NA系统可用于治疗神经病理性疼痛的机制。 与公共卫生相关：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自然的止痛机制，在这个方案中，我们将研究加巴喷丁如何刺激身体自身的止痛系统在慢性疼痛中发挥作用。