Role of the cysteine protease cathepsin S in neuropathic hyperalgesia
Role of the cysteine protease cathepsin S in neuropathic hyperalgesia
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DOI：
10.1016/j.pain.2006.11.017
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发表时间：
2007-08-01
期刊：
影响因子：
7.4
通讯作者：
Malcangio, Marzia
中科院分区：
文献类型：
--
作者：
Barclay, Jane;Clark, Anna K.;Malcangio, Marzia
采用基因表达分析方法，我们发现编码溶酶体半胱氨酸蛋白酶组织蛋白酶S （CatS）的mRNA在大鼠周围神经损伤后的背根神经节（DRG）中上调。在DRG和损伤部位附近的浸润性巨噬细胞中表达CatS蛋白。损伤后第3天至第14天，两个部位的cat表达逐渐增加。在初生大鼠足底注射活化的大鼠重组（rr） cat （0.3, 1 μ g/大鼠）诱导机械性痛觉过敏，在半小时内发生，3小时后减轻，24小时后消失。与活化的rrCatS相比，足底注射活化的rrCathepsin B （CatB）和非活化的rrCatS以相同或更高的剂量对大鼠伤害阈值没有影响。在神经损伤大鼠中，通过全身给药一种非脑渗透的、不可逆的cat抑制剂（LHVS, 3- 30mg /kg s.c），机械性痛觉过敏，而非异常性痛觉，在长达3个月的时间内显著逆转。静脉注射氯丙酸脂质体胶囊（1ml, 5mg /ml）消耗外周巨噬细胞部分减轻了已建立的机械性痛觉过敏，但没有异常性疼痛。消除了LHVS的抗痛觉作用。我们的研究结果证明了cat的促伤害作用，并表明外周巨噬细胞释放的内源性cat有助于神经损伤后神经性痛觉过敏的维持。(C) 2006国际疼痛研究协会。Elsevier B.V.版权所有。
Using a gene expression analysis approach we found that the mRNA encoding the lysosomal cysteine protease cathepsin S (CatS) was up-regulated in rat dorsal root ganglia (DRG) following peripheral nerve injury. CatS protein was expressed in infiltrating macrophages in DRG and near the site of injury. At both sites CatS expression progressively increased from day 3 to day 14 after injury. In naive rats, intraplantar injection of activated rat recombinant (rr) CatS (0.3, 1 mu g/rat) induced a mechanical hyperalgesia that developed within lialf-an-hour, diminished by 3 h and was absent after 24 h. Activated rrCathepsin B (CatB) and non-activated rrCatS injected intraplantarly at the same or higher doses than activated rrCatS had no effect on rat nociceptive thresholds. In nerve-injured rats, mechanical hyperalgesia, but not allodynia, was significantly reversed for up to 3 It by systemic administration of a non-brain penetrant, irreversible CatS inhibitor (LHVS, 3-30 mg/kg s.c.). Depletion of peripheral macrophages by intravenous injection of liposome encapsulate clodronate (1 ml, 5 mg/ml) partially reduced established mechanical hyperalgesia but not allodynia. and abolished the anti-hyperalgesic effect of LHVS. Our results demonstrate a pro-nociceptive effect of CatS and indicate that endogenous CatS released by peripheral macrophages contributes to the maintenance of neuropathic hyperalgesia following nerve injury. (C) 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.