Mechanisms of Pain Associated with Trigeminal Nerve Injury

三叉神经损伤相关的疼痛机制

• 批准号: 10459477
• 负责人: MICHAEL S GOLD
• 金额: $ 55.18万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10459477
• 关键词: Action Potentials; Address; Agonist; Animal Model; Attenuated; Axon; Behavioral; Cadaver; Carbamazepine; Clinical; Data; Development; Electrophysiology (science); Family; Female; Ganglia; Genes; Human; Hypersensitivity; Injury; Knowledge; Light; Mechanics; Modeling; Molecular; Multiple Sclerosis; Nerve; Nerve compression syndrome; Neural Conduction; Organ Donor; Pain; Pain management; Patients; Pattern; Peripheral Nerves; Persistent pain; Pharmaceutical Preparations; Pharmacology; Picrotoxin; Positioning Attribute; Proteins; Rattus; Rodent; Role; Seizures; Site; Societies; Spinal Ganglia; Structure of trigeminal ganglion; Suggestion; Testing; Therapeutic; Therapeutic Effect; Treatment Efficacy; Trigeminal Neuralgia; Trigeminal Pain; Trigeminal System; Trigeminal nerve structure; Up-Regulation; Western Blotting; Woman; animal data; behavioral study; channel blockers; chronic constriction injury; density; design; effective therapy; experimental study; human tissue; injured; knock-down; loved ones; male; men; nerve injury; new therapeutic target; novel; novel therapeutic intervention; pain behavior; pain relief; painful neuropathy; pre-clinical; receptor; response; response to injury; rho; sciatic nerve; sciatic nerve injury; therapeutic target; therapeutically effective; voltage

Trigeminal nerve injury pain remains a significant problem both because of its intensity and persistence, and the absence of consistently effective therapeutic options. The clinical observations that the anti-seizure drug carbamazepine (CBZ) has generally failed in the treatment of somatic nerve injury pain, but helps with trigeminal nerve injury pain, at least temporarily, suggests it may be possible to identify more effective treatments for trigeminal nerve injury pain by identifying the basis for the difference(s) between somatic and trigeminal nerves in response to injury. Pursuing this possibility, we confirmed that CBZ was more effective at relieving ongoing pain and mechanical hypersensitivity in rats associated with an injury to trigeminal than a somatic nerve. Because the same injury (chronic constriction injury (CCI)) was applied to the sciatic nerve (SN) and the infraorbital nerve (ION), these data suggest that the therapeutic efficacy of CBZ reflects a unique response to injury rather than a unique feature of the way the nerve is injured in patients. Consistent with this suggestion we observed an increase in the potency and efficacy of CBZ-induced block of action potential propagation in isolated nerves following ION-CCI but not SN-CCI. This suggests that the therapeutic selectivity of CBZ is due, at least in part, to an action on primary afferents. Our observations that ION-CCI was associated with an increase in NaV1.1 protein and the efficacy of an NaV1.1 preferring channel blocker suggest that this subunit may not only contribute to trigeminal nerve injury pain, but the therapeutic selectivity of CBZ (generally thought of as a voltage-gated Na+ channel (VGSC) blocker). CBZ is also a GABAA receptor agonist and we observed an ION-CCI-induced increase in the potency and efficacy of CBZ on the isolated trigeminal nerve that was reversed by a GABAA receptor blocker. Furthermore, ION-CCI but not SN-CCI was associated with an increase in expression of GABAAρ3, and hypersensitivity associated with ION-CCI, but not SN-CCI was attenuated by a GABAA receptor agonist with activity at GABAA receptors with ρ-subunits. These discoveries uniquely positioned us to determine why the site of nerve injury influences the efficacy of CBZ. We have proposed to do so in experiments described under three Specific Aims designed to test the hypothesis that the ongoing pain and hypersensitivity associated with trigeminal but not somatic nerve injury are due to an increase in NaV1.1, while the selective therapeutic effect of CBZ is due to an increase in both NaV1.1 and GABAAρ3 receptors along the trigeminal nerve. In Aims 1 and 2 we will determine the contribution of VGSCs and GABAA receptor subtypes to trigeminal nerve injury-induced hypersensitivity and the selective therapeutic utility of CBZ. Finally, to validate these preclinical observations, in Aim 3 we will characterize the functional VGSCs and GABAA receptor subunits in human trigeminal and somatic nerves, including trigeminal nerves from patients suffering from trigeminal pain. Together, the results of these experiments will increase our understanding of the role of two key channel types in neuropathic pain and may suggest more effective ways to treat pain associated with trigeminal nerve injury.

三叉神经损伤疼痛仍然是一个重大问题，因为它的强度和持续性，以及 缺乏持续有效的治疗选择。抗惊厥药物的临床观察 卡马西平 (CBZ) 在治疗躯体神经损伤疼痛方面通常失败，但对三叉神经有帮助 神经损伤疼痛，至少是暂时的，表明可能找到更有效的治疗方法 通过识别躯体神经和三叉神经之间差异的基础来治疗三叉神经损伤疼痛 以应对受伤。追求这种可能性，我们确认 CBZ 在缓解持续的压力方面更有效 大鼠的疼痛和机械过敏与三叉神经损伤相关，而不是躯体神经损伤。因为 坐骨神经（SN）和眶下神经受到相同的损伤（慢性压迫性损伤（CCI）） （ION），这些数据表明 CBZ 的治疗效果反映了对损伤的独特反应，而不是 患者神经损伤方式的独特之处。与此建议一致，我们观察到 CBZ 诱导的离体神经动作电位传播阻滞的效力和功效增加 遵循 ION-CCI，但不遵循 SN-CCI。这表明 CBZ 的治疗选择性至少部分归因于： 对初级传入神经的作用。我们观察到 ION-CCI 与 NaV1.1 的增加相关 蛋白和 NaV1.1 偏好通道阻断剂的功效表明，该亚基可能不仅有助于 对三叉神经损伤疼痛的影响，但 CBZ（通常被认为是电压门控 Na+）的治疗选择性 通道（VGSC）阻断剂）。 CBZ 也是 GABAA 受体激动剂，我们观察到 ION-CCI 诱导的增加 CBZ 对被 GABAA 受体逆转的离体三叉神经的效力和功效 拦截器。此外，ION-CCI 而不是 SN-CCI 与 GABAAρ3 表达的增加相关，并且 GABAA 受体激动剂可减弱与 ION-CCI 相关的超敏反应，但与 SN-CCI 无关 具有 ρ 亚基的 GABAA 受体的活性。这些发现使我们能够确定为什么该网站 神经损伤的程度影响CBZ的疗效。我们建议在以下三个描述的实验中这样做 具体目标旨在检验以下假设：持续的疼痛和过敏与 三叉神经损伤而非躯体神经损伤是由于 NaV1.1 增加所致，而选择性治疗 CBZ 的作用是由于三叉神经沿线的 NaV1.1 和 GABAAρ3 受体增加。 在目标 1 和 2 中，我们将确定 VGSC 和 GABAA 受体亚型对三叉神经的贡献 损伤引起的超敏反应和 CBZ 的选择性治疗效用。最后，验证这些临床前 观察结果，在目标 3 中，我们将表征人类中功能性 VGSC 和 GABAA 受体亚基 三叉神经和躯体神经，包括来自患有三叉神经疼痛的患者的三叉神经。一起， 这些实验的结果将加深我们对两种关键通道类型的作用的理解 神经性疼痛，并可能提出更有效的方法来治疗与三叉神经损伤相关的疼痛。