Modulation of Tight Junction Proteins in the Perineurium to Facilitate Peripheral Opioid Analgesia
Modulation of Tight Junction Proteins in the Perineurium to Facilitate Peripheral Opioid Analgesia
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DOI：
10.1097/aln.0b013e318256eeeb
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发表时间：
2012-06-01
期刊：
影响因子：
8.8
通讯作者：
Brack, Alexander
中科院分区：
文献类型：
--
作者：
Rittner, Heike L.;Amasheh, Salah;Brack, Alexander
背景：外周应用阿片类药物可减轻炎性疼痛，但对大鼠和人类患者的非炎症组织效果较差。高渗溶液可促进亲水性阿片类药物在体内非炎症组织的抗伤害性作用。然而，潜在的机制还没有被很好地理解。我们推测阿片类药物的药效增强可能是由于开放了紧密连接蛋白Claudin-1所形成的神经周围屏障。观察阿片类药物脑啡肽(DAMGO)局部应用后的疼痛行为(n=6)和电生理记录(n=9)。结果：局部应用10%氯化钠可提高DAMGO的机械伤害性阈值，促进辣根过氧化物酶对神经的穿透，降低C-而不是A-增量感受器对机械刺激的反应。在非炎症性足爪组织中，Claudin-1表达于表皮、血管和神经膜，周围神经元对降钙素基因相关肽或蛋白基因产物9.5呈免疫反应。经10%氯化钠预处理后，Claudin-1显著降低，而claudin-5和occludin无明显变化。足底应用金属蛋白酶抑制剂(GM6001)可完全逆转上述效应。结论：高渗盐水通过激活金属蛋白酶和调节claudin-1开放神经周围屏障，从而允许亲水性药物进入外周阿片受体。这一原理可能被用来专门针对外周神经元的亲水性药物。
Background: Peripheral application of opioids reduces inflammatory pain but is less effective in noninflamed tissue of rats and human patients. Hypertonic solutions can facilitate the antinociceptive activity of hydrophilic opioids in noninflamed tissue in vivo. However, the underlying mechanisms are not well understood. We hypothesized that the enhanced efficacy of opioids may be because of opening of the perineurial barrier formed by tight junction-proteins like claudin-1.Methods: Male Wistar rats were treated intraplantarly with 10% NaCl. Pain behavior (n = 6) and electrophysiological recordings (n = 9 or more) from skin-nerve preparations after local application of the opioid [d-Ala2, N-Me-Phe4, Gly5-ol]enkephalin (DAMGO) were explored. Tight junction-proteins as well as permeability of the barrier were examined by immunohistochemistry and Western blot (n = 3 or more).Results: Local administration of 10% NaCl facilitated increased mechanical nociceptive thresholds in response to DAMGO, penetration of horseradish peroxidase into the nerve, as well as a reduced response of C-but not A delta-nociceptors to mechanical stimulation after application of DAMGO in the skin-nerve preparation. In noninflamed paw tissue, claudin-1 was expressed in the epidermis, blood vessels, and the perineurium, surrounding neurons immunoreactive for calcitonin gene-related peptide or protein gene product 9.5. Claudin-1 but not claudin-5 or occludin was significantly reduced after pretreatment with 10% NaCl. Intraplantar application of a metalloproteinase inhibitor (GM6001) completely reversed these effects.Conclusion: Hypertonic saline opens the perineurial barrier via metalloproteinase activation and claudin-1 regulation, thereby allowing access of hydrophilic drugs to peripheral opioid receptors. This principle may be used to specifically target hydrophilic drugs to peripheral neurons.