Differential Efficacy of Ketamine in the Acute versus Chronic Stages of Complex Regional Pain Syndrome in Mice.
Differential Efficacy of Ketamine in the Acute versus Chronic Stages of Complex Regional Pain Syndrome in Mice.
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DOI：
10.1097/aln.0000000000000889
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发表时间：
2015-12
期刊：
影响因子：
8.8
通讯作者：
Clark JD
中科院分区：
文献类型：
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作者：
Tajerian M;Leu D;Yang P;Huang TT;Kingery WS;Clark JD
复杂性区域疼痛综合征(CRPS)是一种疼痛、致残且常为慢性的疾病，许多患者从周围神经源性炎症的急性期过渡到具有明显中枢神经系统(CNS)改变的慢性期。氯胺酮是一种中枢作用剂，据信通过阻断N-甲基-D-天冬氨酸(NMDA)受体发挥作用，正越来越多地被用于治疗难治性CRPS，尽管该药物在综合征不同阶段的效果和疗效的基础尚不清楚。我们采用小鼠胫骨骨折/石膏固定的CRPS模型(n=8-12/组)，检测急性期(骨折后3周)和慢性(骨折后7周)氯胺酮(2 mg/kg/d；7天)或赋形剂输注的疗效。急性期骨折小鼠表现出肢体温度升高、水肿和伤害性敏感化，而氯胺酮并不能减轻这些症状。在慢性期使用氯胺酮治疗的骨折小鼠显示伤害性敏感度降低，并持续到输液完成后。在这一慢性期，氯胺酮还减少了潜在的伤害性敏感化，并在骨折后18周改善了运动功能。没有发现输液的副作用。这些行为改变与脊髓星形胶质细胞激活和痛相关蛋白表达的改变有关，这些蛋白包括NMDA受体2b(NR2B)、钙/钙调素依赖的蛋白激酶II(CaMK2)和脑源性神经营养因子(BNDF)。总而言之，这些结果表明氯胺酮在慢性但不是急性期CRPS是有效的，这表明中枢作用药物在早期CRPS中相对无效，因为外周机制对支持伤害性敏感化更关键。
Complex regional pain syndrome (CRPS) is a painful, disabling and often chronic condition, where many patients transition from an acute phase with prominent peripheral neurogenic inflammation to a chronic phase with evident central nervous system (CNS) changes. Ketamine is a centrally-acting agent believed to work through blockade of N-methyl-D-aspartate (NMDA) receptors and is being increasingly used for the treatment of refractory CRPS, although the basis for the drug’s effects and efficacy at different stages of the syndrome remain unclear. We used a mouse model of CRPS (n=8–12/group) involving tibia fracture/cast immobilization to test the efficacy of ketamine (2 mg/kg/day; 7 days) or vehicle infusion during acute (3weeks [3w] post-fracture) and chronic (7w post-fracture) stages. Acute phase fracture mice displayed elevated limb temperature, edema and nociceptive sensitization that were not reduced by ketamine. Fracture mice treated with ketamine during the chronic phase showed reduced nociceptive sensitization that persisted beyond completion of the infusion. During this chronic phase, ketamine also reduced latent nociceptive sensitization and improved motor function at 18 weeks post-fracture. No side effects of the infusions were identified. These behavioral changes were associated with altered spinal astrocyte activation and expression of pain-related proteins including NMDA receptor 2b (NR2b), Ca2+/calmodulin-dependent protein kinase ii (CaMK2), and brain-derived neurotrophic factor (BNDF). Collectively, these results demonstrate that ketamine is efficacious in the chronic, but not acute stages of CRPS, suggesting that the centrally-acting drug is relatively ineffective in early CRPS when peripheral mechanisms are more critical for supporting nociceptive sensitization.