Hedgehog signaling regulates nociceptive sensitization.
Hedgehog signaling regulates nociceptive sensitization.
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DOI：
10.1016/j.cub.2011.08.020
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发表时间：
2011-09-27
期刊：
影响因子：
9.2
通讯作者：
Galko, Michael J.
中科院分区：
文献类型：
--
作者：
Babcock, Daniel T.;Shi, Shanping;Jo, Juyeon;Shaw, Michael;Gutstein, Howard B.;Galko, Michael J.
痛觉致敏是一种组织损伤反应，即受损组织附近的感觉神经元对外部刺激的反应增强。这种致敏表现为异常性疼痛（对先前无害的刺激产生厌恶性退缩）和/或痛觉过敏（对有害刺激的反应过度）。虽然一些介导伤害性致敏的因素是已知的，但目前镇痛药物的不足促使人们寻找其他靶点。在这里，我们使用果蝇热痛觉致敏模型来表明，在紫外线照射（UV）诱导的组织损伤后，热异常性痛觉和痛觉过敏都需要Hedgehog （Hh）信号。致敏似乎不是由伤害感觉神经元分化或树突化的发育变化引起的。遗传分析表明，Hh信号通路与肿瘤坏死因子（TNF）信号通路并行介导异位性痛觉，不同的瞬时受体电位（TRP）通道介导这些通路下游的异位性痛觉和痛觉过敏。我们也证明了Hh在哺乳动物镇痛信号传导中的作用。鞘内或外周给予环巴胺（CP），一种Sonic Hedgehog信号的特异性抑制剂，在大鼠炎症性疼痛的标准实验中阻断了吗啡镇痛耐受（MS）或吗啡抗痛觉的发展，在神经性疼痛的实验中协同增强和持续吗啡镇痛。我们证明了Hh信号的一个新的生理作用，以前没有涉及伤害感觉。我们的研究结果还确定了疼痛治疗的新潜在治疗靶点。
Nociceptive sensitization is a tissue damage response whereby sensory neurons near damaged tissue enhance their responsiveness to external stimuli. This sensitization manifests as allodynia (aversive withdrawal to previously nonnoxious stimuli) and/or hyperalgesia (exaggerated responsiveness to noxious stimuli). Although some factors mediating nociceptive sensitization are known, inadequacies of current analgesic drugs have prompted a search for additional targets. Here we use a Drosophila model of thermal nociceptive sensitization to show that Hedgehog (Hh) signaling is required for both thermal allodynia and hyperalgesia following ultraviolet irradiation (UV)-induced tissue damage. Sensitization does not appear to result from developmental changes in the differentiation or arborization of nociceptive sensory neurons. Genetic analysis shows that Hh signaling acts in parallel to tumor necrosis factor (TNF) signaling to mediate allodynia and that distinct transient receptor potential (TRP) channels mediate allodynia and hyperalgesia downstream of these pathways. We also demonstrate a role for Hh in analgesic signaling in mammals. Intrathecal or peripheral administration of cyclopamine (CP), a specific inhibitor of Sonic Hedgehog signaling, blocked the development of analgesic tolerance to morphine (MS) or morphine antinociception in standard assays of inflammatory pain in rats and synergistically augmented and sustained morphine analgesia in assays of neuropathic pain. We demonstrate a novel physiological role for Hh signaling, which has not previously been implicated in nociception. Our results also identify new potential therapeutic targets for pain treatment.
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