BDNF Signal Strength Modulates NRTI-Induced Allodynia in the Mouse

描述(由申请人提供)：HIV感染最使人虚弱的神经系统并发症之一是与核苷逆转录酶抑制剂(NRTI)相关的痛性周围神经病变(PPN)。主要症状是剧痛和持续的疼痛，对传统的药物治疗具有抵抗力，并可能干扰生活质量。最近，我们做了一个新的观察，几个参加运动临床试验的NRTI诱导的PPN患者报告说，在开始该计划后，疼痛较少，在跑步机上花费的时间更多。我们建立了一种NRTI诱发的痛觉异常的小鼠模型，以研究药物引起的痛觉异常的机制和运动的止痛效果。接受药物治疗的小鼠出现了严重的痛觉异常，仅仅六天的自愿车轮跑步就显着减少了这种疼痛。由于脑源性神经营养因子(BDNF)的表达会随着神经损伤和运动的改变而改变，因此它是调节药物性痛觉过敏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)内BDNF表达的增加通过激活N-甲基-D-天冬氨酸受体(NMDAR)来促进痛觉过敏，NMDAR参与伤害性神经元的活动依赖性终末。通过有氧运动进一步增加SDH神经损伤水平以上BDNF的表达，导致BDNF受体原肌球蛋白相关激酶B(trkB.FL)的显著下调和NMDAR的激活，从而产生镇痛作用。为了支持这一假设，我们证明了鞘内注射外源性BDNF的剂量已被证明下调trkB.FL废除了NRTI诱导的同种异体睡眠症，我们有证据表明，运动小鼠的SDH中trkB.FL的磷酸化显著减少。此外，缺乏trkB.FL的主要负性抑制因子trkB.TI的动物不会发生NRTI诱导的痛觉异常，这可能是由于背角神经元长期暴露在高BDNF水平所致。因此，我们建议BDNF信号在SDH中作为一种“音量控制”机制来调节NRTI诱导的伤害性感受的发展和持续，我们将在本提案中详细探讨这一点。外行语言：艾滋病毒携带者的一个常见问题是他们的药物导致腿部剧烈疼痛，而止痛药并不起作用。这项研究可能会帮助我们更好地了解这种类型的疼痛，以便我们能够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.