Department of Neurobiology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States.
Department of Neurobiology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, United States.
Brain Behav Immun. 2023 Jan;107:215-224. doi: 10.1016/j.bbi.2022.10.013. Epub 2022 Oct 21.
Previously we developed a murine model in which postinjury stimulation of an injured area triggers a transition to a nociplastic pain state manifesting as persistent mechanical hypersensitivity outside of the previously injured area. This hypersensitivity was maintained by sex-specific mechanisms; specifically, activated spinal microglia maintained the hypersensitivity only in males. Here we investigated whether spinal microglia drive the transition from acute injury-induced pain to nociplastic pain in males, and if so, how they are activated by normally innocuous stimulation after peripheral injury. Using intraplantar capsaicin injection as an acute peripheral injury and vibration of the injured paw as postinjury stimulation, we found that inhibition of spinal microglia prevents the vibration-induced transition to a nociplastic pain state. The transition was mediated by the ATP-P2X4 pathway, but not BDNF-TrkB signaling. Intrathecally injected GABA receptor agonists after intraplantar capsaicin injection prevented the vibration-induced transition to a nociplastic pain state. Conversely, in the absence of intraplantar capsaicin injection, intrathecally injected GABA receptor antagonists allowed the vibration stimulation of a normal paw to trigger the transition to a spinal microglia-mediated nociplastic pain state only in males. At the spinal level, TNF-α, IL-1β, and IL-6, but not prostaglandins, contributed to the maintenance of the nociplastic pain state in males. These results demonstrate that in males, the transition from acute injury-induced pain to nociplastic pain is driven by spinal microglia causing neuroinflammation and that peripheral injury-induced spinal GABAergic disinhibition is pivotal for normally innocuous stimulation to activate spinal microglia.
此前，我们开发了一种小鼠模型，在该模型中，损伤区域的损伤后刺激会引发一种转变，即转变为表现为先前损伤区域以外持续机械性超敏的伤害感受性疼痛状态。这种超敏反应是由性别特异性机制维持的；具体来说，激活的脊髓小胶质细胞仅在雄性中维持超敏反应。在这里，我们研究了脊髓小胶质细胞是否在雄性中驱动急性损伤诱导性疼痛向伤害感受性疼痛的转变，如果是这样，它们在周围损伤后如何被正常无害刺激激活。我们使用足底皮内辣椒素注射作为急性外周损伤，并用受伤爪子的振动作为损伤后刺激，发现抑制脊髓小胶质细胞可防止振动诱导向伤害感受性疼痛状态的转变。这种转变是由 ATP-P2X4 途径介导的，但不是 BDNF-TrkB 信号介导的。足底皮内注射辣椒素后鞘内注射 GABA 受体激动剂可防止振动诱导向伤害感受性疼痛状态的转变。相反，在没有足底皮内注射辣椒素的情况下，鞘内注射 GABA 受体拮抗剂允许正常爪子的振动刺激仅在雄性中引发脊髓小胶质细胞介导的伤害感受性疼痛状态的转变。在脊髓水平，TNF-α、IL-1β 和 IL-6，但不是前列腺素，有助于维持雄性的伤害感受性疼痛状态。这些结果表明，在雄性中，急性损伤诱导性疼痛向伤害感受性疼痛的转变是由脊髓小胶质细胞引起的神经炎症驱动的，而周围损伤诱导的脊髓 GABA 能抑制失活对于正常无害刺激激活脊髓小胶质细胞至关重要。
