Mechanisms of 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， 缺乏持续有效的治疗选择。抗癫痫药物的临床观察 卡马西平（CBZ）通常在治疗躯体神经损伤疼痛方面失败，但有助于三叉神经痛， 神经损伤疼痛，至少是暂时的，表明可能有可能找到更有效的治疗方法， 三叉神经损伤疼痛通过识别躯体神经和三叉神经之间差异的基础 以应对伤害。追求这种可能性，我们证实，CBZ是更有效地缓解正在进行的 疼痛和机械性超敏反应在大鼠中与三叉神经的损伤相关，而不是躯体神经。因为 对坐骨神经（SN）和眶下神经施加相同的损伤（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，而不是对损伤的反应。 患者神经损伤方式的独特性。与这一建议相一致，我们观察到 在离体神经中CBZ诱导的动作电位传播阻滞的效力和功效增加 在ION-CCI之后，而不是SN-CCI。这表明CBZ的治疗选择性至少部分是由于， 对初级传入神经的作用。我们观察到ION-CCI与NaV1.1增加有关， 蛋白质和NaV1.1偏好通道阻断剂的功效表明，该亚基可能不仅有助于 但CBZ（通常认为是电压门控性Na+通道）的治疗选择性 通道（VGSC）阻断剂）。CBZ也是一种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 修颜乳液此外，ION-CCI而非SN-CCI与GABAAρ3表达的增加相关， 与ION-CCI相关的超敏反应，而不是SN-CCI，被GABAA受体激动剂减弱， GABAA受体与ρ-亚基的活性。这些发现使我们能够确定 影响CBZ的疗效。我们建议在三个实验中这样做。 特定目的旨在检验以下假设： 三叉神经而不是躯体神经损伤是由于NaV1.1的增加，而选择性治疗 CBZ的作用是由于沿三叉神经的NaV 1.1和GABAAρ3受体沿着增加。 在目的1和2中，我们将确定VGSC和GABAA受体亚型对三叉神经的贡献。 损伤诱导的超敏反应和CBZ的选择性治疗效用。为了验证这些临床前 在目的3中，我们将描述人类VGSC和GABAA受体亚单位的功能， 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。在一起， 这些实验的结果将增加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。

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.