Department of Neuroscience, Cell Biology, and Anatomy, University of Texas Medical Branch, Galveston, TX, United States.
Pain. 2022 Mar 1;163(3):461-473. doi: 10.1097/j.pain.0000000000002366.
Acute injury-induced pain can transition to chronic nociplastic pain, which predominantly affects women. To facilitate studies on the underlying mechanisms of nociplastic pain, we developed a mouse model in which postinjury thermal stimulation (intermittent 40°C water immersion for 10 minutes at 2 hours postcapsaicin) prolongs capsaicin (ie, experimental injury)-induced transient mechanical hypersensitivity outside of the injury area. Although capsaicin injection alone induced mechanical and thermal hypersensitivity that resolved in ∼7 days (slower recovery in females), the postinjury stimulation prolonged capsaicin-induced mechanical, but not thermal, hypersensitivity up to 3 weeks in both sexes. When postinjury stimulation was given at a lower intensity (30°C) or at later time points (40°C at 1-3 days postcapsaicin), chronification of mechanical hypersensitivity occurred only in females. Similar chronification could be induced by a different postinjury stimulation modality (vibration of paw) or with a different injury model (plantar incision). Notably, the 40°C postinjury stimulation did not prolong capsaicin-induced inflammation in the hind paw, indicating that the prolonged mechanical hypersensitivity in these mice arises without clear evidence of ongoing injury, reflecting nociplastic pain. Although morphine and gabapentin effectively alleviated this persistent mechanical hypersensitivity in both sexes, sexually dimorphic mechanisms mediated the hypersensitivity. Specifically, ongoing afferent activity at the previously capsaicin-injected area was critical in females, whereas activated spinal microglia were crucial in males. These results demonstrate that postinjury stimulation of the injured area can trigger the transition from transient pain to nociplastic pain more readily in females, and sex-dependent mechanisms maintain the nociplastic pain state.
急性损伤引起的疼痛可转变为慢性神经病理性疼痛，这种疼痛主要影响女性。为了促进对神经病理性疼痛潜在机制的研究，我们开发了一种小鼠模型，其中损伤后热刺激（在辣椒素注射后 2 小时，用 40°C 的水间歇性浸泡 10 分钟）延长了辣椒素（即实验性损伤）诱导的损伤区域外的短暂机械性超敏反应。尽管单独注射辣椒素会引起机械和热超敏反应，但在 7 天内（女性恢复较慢）会缓解，但损伤后的刺激会使辣椒素诱导的机械超敏反应延长至 3 周，在两性中均如此。当损伤后的刺激强度较低（30°C）或时间点较晚（在辣椒素注射后 1-3 天用 40°C）时，机械性超敏反应仅在雌性中发生慢性化。类似的慢性化可以通过不同的损伤后刺激方式（爪子振动）或不同的损伤模型（足底切口）诱导。值得注意的是，损伤后的 40°C 刺激不会延长后爪中辣椒素诱导的炎症，表明这些小鼠的机械性超敏反应延长没有明显的持续损伤迹象，反映出神经病理性疼痛。虽然吗啡和加巴喷丁能有效缓解两性的这种持续机械性超敏反应，但性别二态性机制介导了超敏反应。具体而言，在先前注射辣椒素的区域持续的传入活动对雌性至关重要，而激活的脊髓小胶质细胞对雄性至关重要。这些结果表明，损伤区域的损伤后刺激更容易在雌性中引发从短暂疼痛向神经病理性疼痛的转变，并且性别依赖性机制维持着神经病理性疼痛状态。
