Department of Psychology and Neuroscience, University of Colorado - Boulder, Boulder, CO, USA.
Department of Engineering, University of Colorado - Boulder, Boulder, CO, USA.
Brain Behav Immun. 2023 Jul;111:177-185. doi: 10.1016/j.bbi.2023.04.002. Epub 2023 Apr 8.
Intrathecal delivery of interleukin-10 (IL-10) gene therapy has been reported to be effective in suppressing pain enhancement in a variety of rodent models. However, all publications that have tested this treatment have relied upon measures of static allodynia (von Frey test) and thermal hyperalgesia (Hargreaves test). As this plasmid DNA IL-10 (pDNA-IL10) therapeutic approach is now in human clinical trials for multiple pain indications, including intrathecal delivery for human neuropathic pain, it is important to consider the recent concerns raised in the pain field that such tests reflect spinal rather than supraspinal processing of, and responsivity to, noxious stimuli. Consequently, this raises the question of whether intrathecal pDNA-IL10 can reverse established neuropathic pain when assessed by a test requiring supraspinal, rather than solely spinal, mediation of the behavioral response. The present study utilizes the rat sciatic chronic constriction injury (CCI) model of neuropathic pain to compare the expression of static allodynia with that of cognitively controlled choice behavior in a two-arm maze, adapted from Hayashida et al. (2019). This modification, termed the Two-Arm Rodent Somatosensory (TARS) task, provides rats free choice to reach a desired goal box via a short "arm" of the maze with tactile probes as flooring versus a longer "arm" of the maze with a smooth surface. Here we demonstrate that static allodynia and avoidance of the nociceptive flooring in TARS develop in parallel over time, and that both behaviors also resolve in parallel following intrathecal pDNA-IL10 gene therapy. Details for the construction and use of this new maze design are also provided. Together, this study documents both: (a) the important finding that intrathecal IL-10 gene therapy does indeed resolve neuropathic pain as measured by a supraspinally-mediated behavioral task, and (b) a new, supraspinally-mediated task that allows behavioral assessments across weeks and allows the analysis of both development and resolution of neuropathic pain by therapeutic interventions. As such, the TARS operant behavior task is an improvement over other approaches such as the mechanical conflict-avoidance system which have difficulties demonstrating development and reversal of pain behavior in a within-subject design.
鞘内递送白细胞介素-10（IL-10）基因治疗已被报道可有效抑制各种啮齿动物模型中的疼痛增强。然而，所有测试这种治疗方法的出版物都依赖于静态触诱发痛（von Frey 测试）和热痛觉过敏（Hargreaves 测试）的测量。由于这种质粒 DNA 白细胞介素-10（pDNA-IL10）治疗方法目前正在针对多种疼痛适应症进行人体临床试验，包括鞘内递用于治疗人类神经性疼痛，因此，重要的是要考虑到疼痛领域最近提出的担忧，即这些测试反映的是有害刺激的脊髓而不是脊髓上加工和反应。因此，这就提出了一个问题，即当通过需要脊髓上而不仅仅是脊髓介导行为反应的测试来评估时，鞘内 pDNA-IL10 是否可以逆转已建立的神经性疼痛。本研究利用大鼠坐骨神经慢性缩窄损伤（CCI）模型的神经性疼痛，比较了静态触诱发痛的表达与在双臂迷宫中的认知控制选择行为的表达，该迷宫改编自 Hayashida 等人（2019 年）。这种修改，称为双臂啮齿动物体感（TARS）任务，为大鼠提供了自由选择，通过迷宫的短“臂”到达期望的目标箱，该短“臂”用触觉探针作为地板，而通过迷宫的长“臂”到达目标箱，该长“臂”的地板是光滑的表面。在这里，我们证明静态触诱发痛和在 TARS 中避免疼痛地板随着时间的推移而平行发展，并且两种行为在鞘内 pDNA-IL10 基因治疗后也平行缓解。本文还提供了这种新型迷宫设计的构建和使用的详细信息。总的来说，这项研究记录了以下两个方面：（a）重要的发现，即鞘内 IL-10 基因治疗确实如通过脊髓上介导的行为任务测量的那样，解决了神经性疼痛；（b）一种新的、脊髓上介导的任务，允许在数周内进行行为评估，并允许通过治疗干预分析神经性疼痛的发展和缓解。因此，TARS 操作性行为任务优于其他方法，例如机械冲突回避系统，后者在个体内设计中难以证明疼痛行为的发展和逆转。
