Zhao Jing, Seereeram Anjan, Nassar Mohammed A, Levato Alessandra, Pezet Sophie, Hathaway Gareth, Morenilla-Palao Cruz, Stirling Caroline, Fitzgerald Maria, McMahon Stephen B, Rios Maribel, Wood John N
Molecular Nociception Group, Department of Biology, University College London, London WC1E 6BT, UK.
Mol Cell Neurosci. 2006 Mar;31(3):539-48. doi: 10.1016/j.mcn.2005.11.008. Epub 2006 Jan 18.
Conditional mouse knock-outs provide an informative approach to drug target validation where no pharmacological blockers exist or global knock-outs are lethal. Here, we used the Cre-loxP system to delete BDNF in most nociceptive sensory neurons. Conditional null animals were healthy with no sensory neuron loss. However, pain-related behavior was substantially altered. Baseline thermal thresholds were reduced. Carrageenan-induced thermal hyperalgesia was inhibited. Formalin-induced pain behavior was attenuated in the second phase, and this correlated with abolition of NMDA receptor NR1 Ser896/897 phosphorylation and ERK1 and ERK2 activation in the dorsal horn; AMPA receptor phosphorylation (GluR1/Ser831) was unaffected. NGF-induced thermal hyperalgesia was halved, and mechanical secondary hyperalgesia caused by intramuscular NGF was abolished. By contrast, neuropathic pain behavior developed normally. Nociceptor-derived BDNF thus plays an important role in regulating inflammatory pain thresholds and secondary hyperalgesia, but BDNF released only from nociceptors plays no role in the development of neuropathic pain.
对于不存在药理学阻断剂或全身性敲除会导致致死的情况，条件性小鼠基因敲除为药物靶点验证提供了一种有效的方法。在此，我们利用Cre-loxP系统在大多数伤害性感觉神经元中删除脑源性神经营养因子（BDNF）。条件性基因缺失动物健康，无感觉神经元丢失。然而，与疼痛相关的行为发生了显著改变。基线热阈值降低。角叉菜胶诱导的热痛觉过敏受到抑制。福尔马林诱导的疼痛行为在第二阶段减弱，这与背角中N-甲基-D-天冬氨酸（NMDA）受体NR1丝氨酸896/897磷酸化以及细胞外信号调节激酶1（ERK1）和细胞外信号调节激酶2（ERK2）激活的消除相关；α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体磷酸化（GluR1/丝氨酸831）未受影响。神经生长因子（NGF）诱导的热痛觉过敏减半，由肌肉内注射NGF引起的机械性继发性痛觉过敏被消除。相比之下，神经性疼痛行为正常发展。因此，伤害感受器衍生的BDNF在调节炎症性疼痛阈值和继发性痛觉过敏中起重要作用，但仅从伤害感受器释放的BDNF在神经性疼痛的发展中不起作用。
