Protraction of neuropathic pain by morphine is mediated by spinal damage associated molecular patterns (DAMPs) in male rats.
Protraction of neuropathic pain by morphine is mediated by spinal damage associated molecular patterns (DAMPs) in male rats.
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DOI：
10.1016/j.bbi.2017.08.018
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Watkins LR
中科院分区：
文献类型：
--
作者：
Grace PM;Strand KA;Galer EL;Rice KC;Maier SF;Watkins LR
我们最近报道，从坐骨神经慢性压迫性损伤（CCI）后10天开始的短期吗啡治疗，延长了吗啡停药后数月的机械性异常性疼痛的持续时间。这种吗啡诱导的持续致敏的维持依赖于脊髓NOD样受体蛋白3（NLRP 3）炎性体-蛋白复合物，其通过caspase-1蛋白水解激活白细胞介素-1 β（IL-1β）。然而，目前尚不清楚NLRP 3炎性体信号传导如何在吗啡清除后维持很长时间。在这里，我们表明，脊髓水平的损伤相关分子模式（DAMPs）高迁移率族蛋白1（HMGB 1）和双糖链蛋白聚糖在吗啡诱导的持续致敏雄性大鼠，即5周后停止吗啡给药。我们还表明，HMGB 1和双糖蛋白聚糖水平至少部分依赖于caspase-1的初始激活，以及Toll样受体4（TLR 4）和嘌呤能受体P2 X7 R-受体，负责引发和激活NLRP 3炎性小体。最后，药理学衰减DAMPs HMGB 1，双糖蛋白聚糖，热休克蛋白90和纤连蛋白持续逆转吗啡延长的异常性疼痛。我们的结论是，周围神经损伤后，吗啡治疗的结果在持续的DAMP释放通过TLR 4，P2 X7 R和caspase-1，参与形成/激活的NLRP 3炎性小体。这些DAMP负责维持持续性异常性疼痛，这可能是由于正反馈环的参与，其中NLRP 3炎性体被DAMP在TLR 4和P2 X7 R处的信号传导持续激活。
We have recently reported that a short course of morphine, starting 10 days after sciatic chronic constriction injury (CCI), prolonged the duration of mechanical allodynia for months after morphine ceased. Maintenance of this morphine-induced persistent sensitization was dependent on spinal NOD-like receptor protein 3 (NLRP3) inflammasomes—protein complexes that proteolytically activate interleukin-1β (IL-1β) via caspase-1. However, it is still unclear how NLRP3 inflammasome signaling is maintained long after morphine is cleared. Here, we demonstrate that spinal levels of the damage associated molecular patterns (DAMPs) high mobility group box 1 (HMGB1) and biglycan are elevated during morphine-induced persistent sensitization in male rats; that is, 5 weeks after cessation of morphine dosing. We also show that HMGB1 and biglycan levels are at least partly dependent on the initial activation of caspase-1, as well as Toll like receptor 4 (TLR4) and the purinergic receptor P2X7R—receptors responsible for priming and activation of NLRP3 inflammasomes. Finally, pharmacological attenuation of the DAMPs HMGB1, biglycan, heat shock protein 90 and fibronectin persistently reversed morphine-prolonged allodynia. We conclude that after peripheral nerve injury, morphine treatment results in persistent DAMP release via TLR4, P2X7R and caspase-1, which are involved in formation/activation of NLRP3 inflammasomes. These DAMPs are responsible for maintaining persistent allodynia, which may be due to engagement of a positive feedback loop, in which NLRP3 inflammasomes are persistently activated by DAMPs signaling at TLR4 and P2X7R.
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吗啡通过TLR4在大鼠脊髓损伤模型中通过TLR4扩增机械性异常。
影响因子：
15.1
作者：
Ellis, Amanda;Grace, Peter M.;Wieseler, Julie;Favret, Jacob;Springer, Kendra;Skarda, Bryce;Ayala, Monica;Hutchinson, Mark R.;Falci, Scott;Rice, Kenner C.;Maier, Steven F.;Watkins, Linda R.
通讯作者：
Watkins, Linda R.
影响因子：
3.7
作者：
Nakamura Y;Morioka N;Abe H;Zhang FF;Hisaoka-Nakashima K;Liu K;Nishibori M;Nakata Y
通讯作者：
Nakata Y
影响因子：
4.8
作者：
Okamura, Y;Watari, M;Strauss, JF
通讯作者：
Strauss, JF
影响因子：
5
作者：
Grace PM;Maier SF;Watkins LR
通讯作者：
Watkins LR
影响因子：
29
作者：
Hoffman, E. Matthew;Watson, James C.;Klein, Christopher J.
通讯作者：
Klein, Christopher J.