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，既是其强​​度和持久性，又是 缺乏一贯有效的治疗选择。抗塞氏菌药物的临床观察 卡马西平（CBZ）通常在治疗躯体神经损伤疼痛方面失败，但有助于三叉神经 至少暂时的神经损伤疼痛表明，有可能确定更有效的治疗方法 三叉神经损伤疼痛通过确定体细胞和三叉神经之间差异的基础 响应伤害。追求这种可能性，我们确认CBZ在缓解持续的情况下更有效 与细胞神经相比，与三叉神经损伤有关的大鼠疼痛和机械性超敏反应。因为 将相同的损伤（慢性狭窄损伤（CCI））应用于坐骨神经（SN）和宽松神经下 （离子）这些数据表明，CBZ的治疗效率反映了对伤害的独特反应，而不是 神经受伤的方式的独特特征。与这个建议一致，我们观察到 孤立神经中CBZ诱导的动作电位传播的效力和效率的提高 遵循离子-CCI，但不是SN-CCI。这表明CBZ的治疗选择性至少部分是由于 采取对主要传入的行动。我们观察到Ion-CCI与NAV1.1的增加有关 蛋白质和NAV1.1首选通道阻滞剂的效率表明，该亚基不仅可能有助于 三叉神经损伤疼痛，但CBZ的治疗选择性（通常被认为是电压门控的Na+ 通道（VGSC）阻止器）。 CBZ也是一种GABAA受体激动剂，我们观察到了离子CCI诱导的增加 在CBZ对隔离的三叉神经上的效力和效率中，该神经被GABAA接收器逆转 阻滞剂。此外，离子-CCI而不是SN-CCI与GabaAρ3表达的增加有关，并且 与离子CCI相关的超敏反应，但没有SN-CCI被GABAA受体激动剂衰减， 在带有ρ-亚基的GABAA受体上的活性。这些发现独特地定位了我们，以确定为什么网站 神经损伤会影响CBZ的效率。我们建议在三个下描述的实验中这样做 具体目的旨在检验以下假设 三叉神经损伤的三叉神经损伤是由于NAV1.1的增加，而选择性治疗 CBZ的影响是由于沿三叉神经沿NAV1.1和GABAAρ3受体的增加所致。 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 损伤引起的过敏性和CBZ的选择性治疗效用。最后，验证这些临床前 观察结果，在AIM 3中，我们将表征人类中的功能性VGSC和GABAA受体亚基 三叉神经和体细胞神经，包括三叉疼痛患者的三叉神经。一起， 这些实验的结果将增加我们对两种关键渠道类型在中的作用的理解 神经性疼痛，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。