Sensitization of cutaneous nociceptors after nerve transection and regeneration: possible role of target-derived neurotrophic factor signaling.
Sensitization of cutaneous nociceptors after nerve transection and regeneration: possible role of target-derived neurotrophic factor signaling.
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DOI：
10.1523/jneurosci.3474-08.2009
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发表时间：
2009-02-11
期刊：
影响因子：
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通讯作者：
Koerber HR
中科院分区：
文献类型：
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作者：
Jankowski MP;Lawson JJ;McIlwrath SL;Rau KK;Anderson CE;Albers KM;Koerber HR
周围神经损伤可导致慢性疼痛状态，包括机械和热痛觉过敏和异常性疼痛。目前尚不清楚这些国家的建立是由于外围变化、中心修改还是两者兼而有之。在这项研究中，我们使用了几种不同的方法来评估隐神经横断和再生后有髓鞘(A)和无髓鞘(C)皮肤伤害感受器的变化。采用离体记录方法研究不同类型功能神经元的反应特征和神经化学表型。我们发现髓鞘伤害感受器在再生后具有较低的机械和热阈值，而c -多模伤害感受器具有较低的热阈值。再生后对热（CHs）有反应的机械不敏感c纤维的百分比显著增加。对鉴定的传入事件进行免疫细胞化学分析发现，naÏve动物中大多数cpm为分离素B4 （IB4）阳性，瞬时受体电位香草素1 （TRPV1）阴性，而CHs均为TRPV1阳性，IB4阴性。然而，再生后，一些鉴定出cpm和CHs两种标记均阳性，这显然是由于IB4阳性神经元总数的增加。对隐神经切开后不同时间L2/L3 DRGs和毛茸茸的后爪皮肤的实时PCR分析表明，神经营养因子信号的多重变化可能与皮肤靶神经的去神经或再神经化有关。这些变化可能是神经再生后观察到的功能改变的基础，并可能解释神经损伤如何导致慢性疼痛状况。
Damage to peripheral nerves is known to contribute to chronic pain states, including mechanical and thermal hyperalgesia and allodynia. It is unknown whether the establishment of these states is due to peripheral changes, central modifications or both. In this study, we used several different approaches to assess the changes in myelinated (A) and unmyelinated (C) cutaneous nociceptors following transection and regeneration of the saphenous nerve. An ex-vivo recording preparation was used to examine response characteristics and neurochemical phenotype of different types of functionally defined neurons. We found that myelinated nociceptors had significantly lower mechanical and thermal thresholds after regeneration, while C-polymodal nociceptors (CPMs) had lower heat thresholds. There was a significant increase in the percentage of mechanically insensitive C-fibers that responded to heat (CHs) after regeneration. Immunocytochemical analysis of identified afferents revealed that most CPMs were isolectin B4 (IB4) positive and transient receptor potential vanilloid 1 (TRPV1) negative, while CHs were always TRPV1 positive and IB4 negative in naÏve animals. However, after regeneration, some identified CPMs and CHs stained positively for both markers, which was apparently due to an increase in the total number of IB4 positive neurons. Realtime PCR analysis of L2/L3 DRGs and hairy hindpaw skin at various times after saphenous nerve axotomy suggested multiple changes in neurotrophic factor signaling that either correlated with denervation or reinnervation of the cutaneous target. These changes may underlie the functional alterations observed after nerve regeneration and may explain how nerve damage leads to chronic pain conditions.