Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA.
Pain Med. 2010 Aug;11(8):1239-50. doi: 10.1111/j.1526-4637.2010.00913.x.
Complex regional pain syndrome (CRPS) patients exhibit multiorgan pathology and inflammatory changes after limb trauma. The objective of this study was to identify how neuro-cutaneous signaling is facilitated after fracture and examine how this altered signaling contributes to the development of CRPS-like changes in the injured limb.
These studies used a rat tibia fracture model that reliably generates hindpaw warmth, edema, increased spontaneous protein extravasation, allodynia, unweighting, and periarticular bone loss, a symptom complex resembling the vascular, nociceptive, and bone sequelae observed in early CRPS. Substance P (SP)-evoked extravasation responses, EIA and PCR assays, and immunohistochemical techniques were used to evaluate post-fracture up-regulation of neuro-cutaneous inflammatory signaling. A SP NK1 receptor antagonist was used to inhibit CRPS-like changes in the fracture model.
In the rat fracture model the SP-evoked extravasation and edema responses were enhanced. SP NK1 receptor expression also increased in the microvascular endothelial cells in the fracture hindpaw skin, leading us to postulate that NK1 receptor up-regulation mediates the facilitated extravasation and edema responses observed after SP injection. The NK1 receptor antagonist LY303870 reversed hindpaw warmth, edema, increased vascular permeability, allodynia, and unweighting observed after tibia fracture in rats. There was also increased keratinocyte proliferation and NK1 receptor expression in the fracture hindpaw. Similar to the rat fracture model, we have observed increased epidermal thickness and keratinocyte NK1 expression in skin biopsies from CRPS patients. There was an up-regulation of inflammatory cytokine expression in the rat hindpaw skin and in keratinocytes at 4 weeks post-fracture. These inflammatory mediators appear to play a crucial role in the development of pain behavior after fracture, as we have repeatedly demonstrated that inhibition of cytokine, and NGF signaling prevents the allodynia and attenuates unweighting at 4 weeks post-fracture. LY303870 treatment also reversed post-fracture keratinocyte proliferation, suggesting that SP might be acting as an intermediate mediator in the inflammatory cascade by causing the up-regulation of inflammatory proteins that can directly sensitize nociceptors in the skin and joints.
Collectively, these data suggest that neuro-cutaneous signaling is up-regulated and can mediate inflammatory changes observed in the hindpaw skin of the fracture rat model and in human CRPS skin. Future translational and clinical studies mapping these inflammatory changes may identify novel therapeutic targets for preventing post-traumatic pain from transitioning into chronic CRPS.
创伤后肢体，复杂区域疼痛综合征（CRPS）患者表现出多器官病理和炎症改变。本研究旨在确定神经皮肤信号如何在骨折后得到促进，并研究这种改变的信号如何导致受伤肢体中出现类似 CRPS 的变化。
这些研究使用了一种可靠地产生后爪温热、水肿、自发性蛋白渗出增加、痛觉过敏、去重和关节周围骨丢失的大鼠胫骨骨折模型，这是一种类似于早期 CRPS 中观察到的血管、伤害感受和骨后遗症的症状复合体。使用 P 物质（SP）诱发的渗出反应、EIA 和 PCR 测定以及免疫组织化学技术来评估骨折后神经皮肤炎症信号的上调。使用 SP NK1 受体拮抗剂抑制骨折模型中类似 CRPS 的变化。
在大鼠骨折模型中，SP 诱发的渗出和水肿反应增强。SP NK1 受体表达也在骨折后爪皮肤的微血管内皮细胞中增加，这使我们推测 NK1 受体上调介导了 SP 注射后观察到的促进渗出和水肿反应。SP NK1 受体拮抗剂 LY303870 逆转了大鼠胫骨骨折后后爪温热、水肿、血管通透性增加、痛觉过敏和去重。在骨折后爪中还观察到角质形成细胞增殖和 NK1 受体表达增加。类似于大鼠骨折模型，我们在 CRPS 患者的皮肤活检中观察到表皮厚度增加和角质形成细胞 NK1 表达增加。在骨折后 4 周时，大鼠后爪皮肤和角质形成细胞中的炎症细胞因子表达上调。这些炎症介质似乎在骨折后疼痛行为的发展中起着至关重要的作用，因为我们已经反复证明，抑制细胞因子和 NGF 信号可以防止骨折后 4 周时的痛觉过敏和减轻去重。LY303870 治疗还逆转了骨折后的角质形成细胞增殖，表明 SP 可能通过引起炎症蛋白的上调而充当炎症级联反应中的中间介质，这些炎症蛋白可以直接敏化皮肤和关节中的伤害感受器。
综上所述，这些数据表明，神经皮肤信号上调，并可介导骨折大鼠模型后爪皮肤和人类 CRPS 皮肤中观察到的炎症变化。未来映射这些炎症变化的转化和临床研究可能会确定预防创伤后疼痛转变为慢性 CRPS 的新治疗靶点。
