Department of Neurology, University Hospital of Würzburg, Würzburg, Germany Department of Neurology, Johannes Gutenberg University Mainz, Mainz, Germany Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Pain. 2014 Mar;155(3):574-580. doi: 10.1016/j.pain.2013.12.003. Epub 2013 Dec 11.
The pathophysiology of the complex regional pain syndrome involves enhanced neurogenic inflammation mediated by neuropeptides. Neutral endopeptidase (neprilysin, NEP) is a key enzyme in neuropeptide catabolism. Our previous work revealed that NEP knock out (ko) mice develop more severe hypersensitivity to thermal and mechanical stimuli after chronic constriction injury (CCI) of the sciatic nerve than wild-type (wt) mice. Because treatment with glucocorticoids is effective in early complex regional pain syndrome, we investigated whether methylprednisolone (MP) reduces pain and sciatic nerve neuropeptide content in NEP ko and wt mice with nerve injury. After CCI, NEP ko mice developed more severe thermal and mechanical hypersensitivity and hind paw edema than wt mice, confirming previous findings. Hypersensitivity was prevented by MP treatment in NEP ko but not in wt mice. MP treatment had no effect on protein levels of calcitonin-gene related peptide, substance P, and bradykinin in sciatic nerves of NEP ko mice. Endothelin-1 (ET-1) levels were higher in naïve and nerve-injured NEP ko than in wt mice, without an effect of MP treatment. Gene expression of the ET-1 receptors ETAR and ETBR was not different between genotypes and was not altered after CCI, but was increased after additional MP treatment. The ETBR agonist IRL-1620 was analgesic in NEP ko mice after CCI, and the ETBR antagonist BQ-788 showed a trend to reduce the analgesic effect of MP. The results provide evidence that MP reduces CCI-induced hyperalgesia in NEP ko mice, and that this may be related to ET-1 via analgesic actions of ETBR.
复杂区域疼痛综合征的病理生理学涉及到神经源性炎症的增强，这种炎症由神经肽介导。中性内肽酶（neprilysin，NEP）是神经肽代谢中的关键酶。我们之前的工作表明，与野生型（wt）小鼠相比，神经肽 NEP 敲除（ko）小鼠在坐骨神经慢性缩窄损伤（CCI）后对热和机械刺激的超敏反应更为严重。由于糖皮质激素在早期复杂区域疼痛综合征的治疗中有效，我们研究了在神经损伤的 NEP ko 和 wt 小鼠中，甲泼尼龙（MP）是否能减轻疼痛和坐骨神经神经肽含量。CCI 后，NEP ko 小鼠比 wt 小鼠表现出更严重的热和机械超敏反应和后爪水肿，这与之前的发现一致。MP 治疗可预防 NEP ko 小鼠的超敏反应，但不能预防 wt 小鼠的超敏反应。MP 治疗对 NEP ko 小鼠坐骨神经中降钙素基因相关肽、P 物质和缓激肽的蛋白水平没有影响。在未受伤和受伤的 NEP ko 小鼠中，内皮素-1（ET-1）水平均高于 wt 小鼠，但 MP 治疗没有影响。ET-1 受体 ETAR 和 ETBR 的基因表达在基因型之间没有差异，CCI 后也没有改变，但在额外的 MP 治疗后增加。CCI 后，ETBR 激动剂 IRL-1620 在 NEP ko 小鼠中具有镇痛作用，而 ETBR 拮抗剂 BQ-788 显示出减少 MP 镇痛作用的趋势。研究结果提供了证据表明，MP 可减轻 NEP ko 小鼠 CCI 诱导的痛觉过敏，这可能与 ET-1 有关，通过 ETBR 的镇痛作用。
