Transient opening of the perineurial barrier for analgesic drug delivery
Transient opening of the perineurial barrier for analgesic drug delivery
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DOI：
10.1073/pnas.1120800109
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发表时间：
2012-07-17
影响因子：
11.1
通讯作者：
Rittner, Heike L.
中科院分区：
文献类型：
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作者：
Hackel, Dagmar;Krug, Susanne M.;Rittner, Heike L.
选择性靶向周围神经中的感觉或伤害性神经元仍然是临床上理想的目标。有前景的镇痛药物的输送常常受到神经束膜的阻碍，神经束膜由于紧密连接而起到扩散屏障的作用。我们使用神经周注射高渗盐水作为工具暂时打开大鼠的神经周围屏障，并详细阐明了分子作用原理：高渗盐水通过金属蛋白酶 9 (MMP9) 发挥作用。 MMP9 的非催化血红素结构域与低密度脂蛋白受体相关蛋白-1 结合，触发细胞外信号调节激酶 1/2 的磷酸化，并诱导屏障形成紧密连接蛋白claudin-1 的下调。腹腔注射该途径的任何成分，包括 MMP9 血红结合蛋白结构域或claudin-1 siRNA，可使阿片肽（[D-Ala2，N-Me-Phe4，Gly5-ol]-脑啡肽）和选择性钠通道（NaV1.7）阻断毒素（ProToxin-II）发挥抗伤害作用，而不会损害运动。后者以及经典的 TTX 仅在神经周围屏障破坏后才阻断孤立神经中的复合动作电位，这反过来又允许神经内释放的降钙素基因相关肽穿过神经鞘。我们的数据确立了神经束膜中claudin-1作为主要密封成分的功能和调节，可以对其进行调节以促进药物输送，或者有可能在病理条件下重新密封屏障。
Selective targeting of sensory or nociceptive neurons in peripheral nerves remains a clinically desirable goal. Delivery of promising analgesic drugs is often impeded by the perineurium, which functions as a diffusion barrier attributable to tight junctions. We used perineurial injection of hypertonic saline as a tool to open the perineurial barrier transiently in rats and elucidated the molecular action principle in mechanistic detail: Hypertonic saline acts via metalloproteinase 9 (MMP9). The noncatalytic hemopexin domain of MMP9 binds to the low-density lipoprotein receptor-related protein-1, triggers phosphorylation of extracellular signal-regulated kinase 1/2, and induces down-regulation of the barrier-forming tight junction protein claudin-1. Perisciatic injection of any component of this pathway, including MMP9 hemopexin domain or claudin-1 siRNA, enables an opioid peptide ([D-Ala2,N-Me-Phe4, Gly5-ol]-enkephalin) and a selective sodium channel (NaV1.7)-blocking toxin (ProToxin-II) to exert antinociceptive effects without motor impairment. The latter, as well as the classic TTX, blocked compound action potentials in isolated nerves only after disruption of the perineurial barrier, which, in return, allowed endoneurally released calcitonin gene-related peptide to pass through the nerve sheaths. Our data establish the function and regulation of claudin-1 in the perineurium as the major sealing component, which could be modulated to facilitate drug delivery or, potentially, reseal the barrier under pathological conditions.