Mechanisms of Pain Associated with Trigeminal Nerve Injury

三叉神经损伤相关的疼痛机制

• 批准号: 10274559
• 负责人: MICHAEL S GOLD
• 金额: $ 54.9万
• 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/10274559
• 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要的问题，因为它的强度和持久性，以及 缺乏一贯有效的治疗选择。抗癫痫药治疗癫痫的临床观察 卡马西平(CBZ)在治疗躯体神经损伤疼痛方面通常失败，但对三叉神经痛有帮助 神经损伤疼痛，至少是暂时的，表明有可能找到更有效的治疗方法 辨体神经与三叉神经区别的基础--三叉神经损伤性疼痛(S) 作为对受伤的反应。追寻这一可能性，我们证实CBZ在缓解正在进行的疾病方面更有效 与三叉神经损伤相关的大鼠的疼痛和机械过敏。因为 对坐骨神经(SN)和眶下神经进行相同的损伤(慢性压迫损伤 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。与这一建议一致，我们观察到 卡马西平阻断离体神经动作电位传播的效力和效果 在ION-CCI之后，但不在SN-CCI之后。这表明，CBZ的治疗选择性至少部分归因于， 对主要传入神经的诉讼。我们观察到ION-CCI与Nav1.1的增加相关 蛋白和Nav1.1首选通道阻滞剂的疗效表明，这个亚基可能不仅对 对三叉神经损伤疼痛，但卡马西平(一般认为是电压门控性钠离子)的治疗选择性 通道(VGSC)阻滞剂)。CBZ也是一种GABAA受体激动剂，我们观察到离子CCI诱导的增加 卡马西平对被GABAA受体逆转的三叉神经的作用 拦截者。此外，离子-CCI而不是SN-CCI与GABAAρ3的表达增加有关，并且 GABAA受体激动剂可减弱离子-CCI相关的超敏反应，但不能减弱SN-CCI的超敏反应 带有ρ亚基的GABAA受体的活性。这些发现使我们能够独特地确定为什么 神经损伤程度影响卡马西平的疗效。我们已经在下面描述的三个实验中提出了这一点 特定的目的旨在检验这样一种假设，即持续的疼痛和过敏与 三叉神经但不是躯体神经损伤是由于Nav1.1的增加，而选择性治疗 卡马西平的作用是由于沿三叉神经的NAV1.1和GAAAρ3受体的增加。 在目标1和目标2中，我们将确定VGSCs和GABAA受体亚型对三叉神经的贡献 损伤超敏反应与卡马西平的选择性治疗作用。最后，为了验证这些临床前 观察，在目标3中，我们将描述人类VGSCs和GABAA受体亚单位的功能 三叉神经和躯体神经，包括三叉神经痛患者的三叉神经。一起， 这些实验的结果将增加我们对两种关键通道类型在 他说，这是一种神经性疼痛，可能会为治疗与三叉神经损伤相关的疼痛提供更有效的方法。