BDNF Signal Strength Modulates NRTI-Induced Allodynia in the Mouse

描述（由申请人提供）：HIV感染最严重的神经系统并发症之一是与核苷逆转录酶抑制剂（NRTI）相关的疼痛性周围神经病变（PPN）。其主要症状是难以忍受的持续疼痛，对传统药物治疗有抵抗力，并可能影响生活质量。最近，我们进行了一项新的观察，几名NRTI诱导的PPN患者参加了一项运动临床试验，报告疼痛减轻，开始计划后在跑步机上花费更多时间。我们建立了NRTI诱导的异常性疼痛的小鼠模型，以研究药物诱发的异常性疼痛的机制和运动的镇痛作用。药物治疗的小鼠出现了严重的异常性疼痛，仅通过6天的自愿轮跑就显着减轻了。由于脑源性神经营养因子（BDNF）的表达在神经损伤和运动中都会发生变化，因此它是调节药物诱导的异常性疼痛和运动保护作用的理想候选者。我们假设神经损伤介导的脊髓背角（SDH）BDNF表达增加通过激活参与伤害性神经元活动依赖性缠绕的N-甲基-D-天冬氨酸受体（NMDAR）促进痛觉过敏。通过有氧运动进一步增加SDH中BDNF表达高于神经损伤水平，导致BDNF受体原肌球蛋白相关激酶B（trk B.FL）的显著下调和NMDAR活化的消除，产生镇痛作用。为了支持这一假设，我们证明，鞘内注射外源性BDNF的剂量，已被证明下调trkB.FL废除NRTI诱导的alloproxynia，我们有证据表明，trkB.FL磷酸化显着减少在SDH的运动小鼠。此外，缺乏trkB.FL的显性负性抑制剂trkB.TI的动物不会发生NRTI诱导的异常性疼痛，这可能是由于背角神经元长期暴露于高BDNF水平所致。因此，我们建议，BDNF信号作为一个“音量控制”机制，在SDH调制的发展和持续性的伤害性刺激诱导的NRTI，我们将在本提案中详细探讨这一点。外行语言：艾滋病毒感染者的一个常见问题是他们的药物引起的腿部剧痛，止痛药没有帮助。这项研究可以帮助我们更好地了解这种类型的疼痛，以便我们找到更好的方法来减轻疼痛。

DESCRIPTION (provided by applicant): One of the most debilitating neurological complications of HIV infection is painful peripheral neuropathy (PPN) associated with nucleoside reverse transcriptase inhibitors (NRTIs). The predominant symptom, excruciating and unremitting pain, is resistant to traditional pharmacological treatment and can interfere with quality of life. Recently, we made the novel observation that several patients with NRTI-induced PPN enrolled in an exercise clinical trial reported less pain and spent more time on treadmill after starting the program. We developed a mouse model of NRTI-induced allodynia to examine the mechanisms underlying drug-evoked allodynia and the analgesic effects of exercise. The drug-treated mice developed profound allodynia that was significantly reduced by just six days of voluntary wheel running. Since Brain-Derived Neurotrophic Factor (BDNF) expression is altered in response to both nerve injury and exercise, it is an ideal candidate to modulate both the drug-induced allodynia and the protective effects of exercise. We hypothesize that a nerve injury-mediated increase in BDNF expression in the spinal dorsal horn (SDH) promotes hyperalgesia by activating N-methyl-D-aspartate receptors (NMDARs) that participate in activity- dependent windup of nociceptive neurons. Further increasing BDNF expression above nerve injury levels in the SDH via aerobic exercise leads to a significant downregulation of the BDNF receptor tropomyosin-related kinase B (trkB.FL) and abrogation of NMDAR activation, producing analgesia. In support of this hypothesis, we demonstrate that intrathecal administration of exogenous BDNF at a dose that has been shown to downregulate trkB.FL abrogates NRTI-induced alloydnia and we have evidence to suggest that trkB.FL phosphorylation is significantly reduced in the SDH of exercised mice. Moreover, animals that lack the dominant negative inhibitor of trkB.FL, trkB.TI, do not develop NRTI-induced allodynia, presumably due to chronic exposure of dorsal horn neurons to high BDNF levels. Thus, we propose that BDNF signaling acts as a "volume control" mechanism in the SDH to modulate the development and persistence of nociception induced by NRTIs, and we will explore this in detail in this proposal. Lay language: A common problem for people with HIV is severe pain in the legs caused by their medications, and pain medicine doesn't help. This study may help us understand this type of pain better so that we can find better ways to reduce pain.