Pain inhibition by blocking leukocytic and neuronal opioid peptidases in peripheral inflamed tissue
Pain inhibition by blocking leukocytic and neuronal opioid peptidases in peripheral inflamed tissue
复制标题
DOI：
10.1096/fj.12-208678
复制
发表时间：
2012-12-01
期刊：
影响因子：
4.8
通讯作者：
Machelska, Halina
中科院分区：
文献类型：
--
作者：
Schreiter, Anja;Gore, Carmen;Machelska, Halina
炎性疼痛可以通过内源性阿片肽来控制。在这里，我们阻断了阿片类药物在外周损伤组织中的降解，以局部增强该生理系统。在具有后爪炎症的大鼠中，将氨肽酶N（APN; bestatin）或中性内肽酶（NEP; thiorphan）的抑制剂和双重抑制剂NH 2-CH-Ph-P（O）（OH）CH 2-CH-CH 2 Ph（p-Ph）-CONH-CH-CH 3-COOH（P8 B）应用于受伤的爪。组合的bestatin（1.25-5 mg）/thiorphan（0.2-0.8 mg）或单独的P8 B（0.0625-1 mg）分别将机械伤害感受阈值提高至载体处理对照的307和227%。甲硫氨酸-脑啡肽、亮氨酸-脑啡肽和强啡肽A 1-17的抗体，外周限制性和选择性μ-、δ-和κ-阿片受体拮抗剂可消除这种镇痛作用。流式细胞术和光谱分析显示APN和NEP在炎症组织的巨噬细胞、粒细胞和坐骨神经上的表达和代谢活性。放射免疫分析表明，抑制白细胞APN和NEP的bestatin（5-500 μ M）/thiorphan（1-100 μ M）组合或P8 B（1-100 μ M）防止脑啡肽的降解。通过bestatin（0.5-10 mM）/thiorphan（0.1-5 mM）或通过P8 B（0.1-10 mM）阻断神经元肽酶另外阻碍强啡肽A1 -17催化。因此，白细胞和外周神经是炎症组织中APN和NEP的重要来源，它们的阻断促进外周阿片类镇痛。Schreiter，A.，戈尔，C.，Labuz，D.，Fournie-Zaluski，M. C.的方法，罗克斯，B。P.的人，Stein，C.，马谢尔斯卡湾通过阻断外周炎症组织中的白细胞和神经元阿片肽酶抑制疼痛。FASEB J.26，5161-5171（2012）。www.fasebj.org
Inflammatory pain can be controlled by endogenous opioid peptides. Here we blocked the degradation of opioids in peripheral injured tissue to locally augment this physiological system. In rats with hindpaw inflammation, inhibitors of aminopeptidase N (APN; bestatin) or neutral endopeptidase (NEP; thiorphan), and a dual inhibitor, NH2-CH-Ph-P(O)(OH)CH2-CH-CH2Ph(p-Ph)-CONH-CH-CH3-COOH (P8B), were applied to injured paws. Combined bestatin (1.25-5 mg)/thiorphan (0.2-0.8 mg) or P8B (0.0625-1 mg) alone elevated mechanical nociceptive thresholds to 307 and 227% of vehicle-treated controls, respectively. This analgesia was abolished by antibodies to methionine-enkephalin, leucine-enkephalin, and dynorphin A 1-17, by peripherally restricted and by selective mu-, delta-, and kappa-opioid receptor antagonists. Flow cytometry and photospectrometry revealed expression and metabolic activity of APN and NEP on macrophages, granulocytes, and sciatic nerves from inflamed tissue. Radioimmunoassays showed that inhibition of leukocytic APN and NEP by bestatin (5-500 mu M)/thiorphan (1-100 mu M) combinations or by P8B (1-100 mu M) prevented the degradation of enkephalins. Blockade of neuronal peptidases by bestatin (0.5-10 mM)/thiorphan (0.1-5 mM) or by P8B (0.1-10 mM) additionally hindered dynorphin A 1-17 catabolism. Thus, leukocytes and peripheral nerves are important sources of APN and NEP in inflamed tissue, and their blockade promotes peripheral opioid analgesia.-Schreiter, A., Gore, C., Labuz, D., Fournie-Zaluski, M.-C., Roques, B. P., Stein, C., Machelska, H. Pain inhibition by blocking leukocytic and neuronal opioid peptidases in peripheral inflamed tissue. FASEB J. 26, 5161-5171 (2012). www.fasebj.org