Division of Biosciences, Ohio State University College of Dentistry, Columbus, Ohio 43210.
Department of Neuroscience.
J Neurosci. 2019 Feb 13;39(7):1139-1149. doi: 10.1523/JNEUROSCI.2785-18.2018. Epub 2018 Dec 17.
Clinical studies indicate that psychosocial stress contributes to adverse chronic pain outcomes in patients, but it is unclear how this is initiated or amplified by stress. Repeated social defeat (RSD) is a mouse model of psychosocial stress that activates microglia, increases neuroinflammatory signaling, and augments pain and anxiety-like behaviors. We hypothesized that activated microglia within the spinal cord facilitate increased pain sensitivity following RSD. Here we show that mechanical allodynia in male mice was increased with exposure to RSD. This stress-induced behavior corresponded with increased mRNA expression of several inflammatory genes, including IL-1β, TNF-α, CCL2, and TLR4 in the lumbar spinal cord. While there were several adhesion and chemokine-related genes increased in the lumbar spinal cord after RSD, there was no accumulation of monocytes or neutrophils. Notably, there was evidence of microglial activation selectively within the nociceptive neurocircuitry of the dorsal horn of the lumbar cord. Elimination of microglia using the colony stimulating factor 1 receptor antagonist PLX5622 from the brain and spinal cord prevented the development of mechanical allodynia in RSD-exposed mice. Microglial elimination also attenuated RSD-induced IL-1β, CCR2, and TLR4 mRNA expression in the lumbar spinal cord. Together, RSD-induced allodynia was associated with microglia-mediated inflammation within the dorsal horn of the lumbar spinal cord. Mounting evidence indicates that psychological stress contributes to the onset and progression of adverse nociceptive conditions. We show here that repeated social defeat stress causes increased pain sensitivity due to inflammatory signaling within the nociceptive circuits of the spinal cord. Studies here mechanistically tested the role of microglia in the development of pain by stress. Pharmacological ablation of microglia prevented stress-induced pain sensitivity. These findings demonstrate that microglia are critical mediators in the induction of pain conditions by stress. Moreover, these studies provide a proof of principle that microglia can be targeted as a therapeutic strategy to mitigate adverse pain conditions.
临床研究表明，心理社会压力会导致患者慢性疼痛不良结局，但目前尚不清楚压力是如何引发或加剧这种情况的。反复社会挫败（RSD）是一种心理社会应激的小鼠模型，可激活小胶质细胞，增加神经炎症信号，并增强疼痛和焦虑样行为。我们假设脊髓内激活的小胶质细胞有助于 RSD 后疼痛敏感性增加。在这里，我们显示雄性小鼠的机械性痛觉过敏在接触 RSD 后增加。这种应激诱导的行为与几种炎症基因（包括白细胞介素 1β、肿瘤坏死因子-α、CCL2 和 TLR4）在腰椎脊髓中的 mRNA 表达增加相对应。虽然 RSD 后腰椎脊髓中有几个黏附分子和趋化因子相关基因增加，但单核细胞或中性粒细胞没有积累。值得注意的是，在腰椎脊髓背角的伤害性神经回路中，有证据表明小胶质细胞选择性激活。用集落刺激因子 1 受体拮抗剂 PLX5622 从大脑和脊髓中消除小胶质细胞可防止 RSD 暴露小鼠发展为机械性痛觉过敏。小胶质细胞消除也减弱了 RSD 诱导的腰椎脊髓中 IL-1β、CCR2 和 TLR4 mRNA 表达。总之，RSD 诱导的痛觉过敏与腰椎脊髓背角中小胶质细胞介导的炎症有关。越来越多的证据表明，心理压力会导致不良伤害性疾病的发生和发展。我们在这里表明，反复的社会挫败应激会导致疼痛敏感性增加，这是由于脊髓伤害性回路中的炎症信号。这些研究从机制上测试了小胶质细胞在应激引起的疼痛发展中的作用。小胶质细胞的药理学消融可防止应激引起的疼痛敏感性。这些发现表明，小胶质细胞是应激引起疼痛状态的关键介质。此外，这些研究提供了一个原理证明，即小胶质细胞可以作为减轻不良疼痛状态的治疗策略的靶点。
