BDNF Signal Strength Modulates NRTI-Induced Allodynia in the Mouse

描述（由申请人提供）：HIV感染最衰弱的神经系统并发症之一是与核苷类逆转录酶抑制剂（NRTIs）相关的疼痛性周围神经病变（PPN）。主要症状是难以忍受和持续的疼痛，传统的药物治疗难以治愈，并可能影响生活质量。最近，我们进行了一项新的观察，在一项运动临床试验中，几名nrti诱导的PPN患者报告说，在开始这项计划后，疼痛减轻了，在跑步机上花了更多的时间。我们建立了nrti诱导的异位性疼痛小鼠模型，以研究药物诱发的异位性疼痛的机制和运动的镇痛作用。经过药物治疗的小鼠出现了严重的异常性痛觉，这种痛觉在六天的自愿跑轮运动后显著减轻。由于脑源性神经营养因子（BDNF）的表达在神经损伤和运动的反应中发生改变，因此它是调节药物性异常性疼痛和运动保护作用的理想候选物。我们假设神经损伤介导的脊髓背角（SDH） BDNF表达的增加通过激活n -甲基- d -天冬氨酸受体（NMDARs）来促进痛觉过敏，NMDARs参与活动依赖性的伤害性神经元的激活。通过有氧运动进一步增加SDH中高于神经损伤水平的BDNF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激活的消除，从而产生镇痛。为了支持这一假设，我们证明鞘内给予外源性BDNF的剂量已被证明可以下调trkB。FL消除nrti诱导的合金，我们有证据表明trkB。在运动小鼠的SDH中，FL磷酸化显著降低。此外，缺乏trkB显性负性抑制剂的动物。FL, trkB。可能是由于背角神经元长期暴露于高BDNF水平，因此不会发生nrti诱导的异常性疼痛。因此，我们提出BDNF信号在SDH中作为一种“体积控制”机制来调节nrti诱导的伤害感受的发展和持续，我们将在本提案中对此进行详细探讨。通俗语言：艾滋病病毒感染者的一个常见问题是药物引起的腿部剧烈疼痛，而止痛药不起作用。这项研究可以帮助我们更好地理解这种类型的疼痛，从而我们可以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.