The Dr. John and Anne Chong Laboratory for Functional Genomics, Charles Perkins Centre and School of Life and Environmental Sciences, The University of Sydney, NSW 2006, Australia.
School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China.
Sci Adv. 2019 Jul 10;5(7):eaaw4099. doi: 10.1126/sciadv.aaw4099. eCollection 2019 Jul.
Injury can lead to devastating and often untreatable chronic pain. While acute pain perception (nociception) evolved more than 500 million years ago, virtually nothing is known about the molecular origin of chronic pain. Here we provide the first evidence that nerve injury leads to chronic neuropathic sensitization in insects. Mechanistically, peripheral nerve injury triggers a loss of central inhibition that drives escape circuit plasticity and neuropathic allodynia. At the molecular level, excitotoxic signaling within GABAergic (γ-aminobutyric acid) neurons required the acetylcholine receptor and led to caspase-dependent death of GABAergic neurons. Conversely, disruption of GABA signaling was sufficient to trigger allodynia without injury. Last, we identified the conserved transcription factor twist as a critical downstream regulator driving GABAergic cell death and neuropathic allodynia. Together, we define how injury leads to allodynia in insects, and describe a primordial precursor to neuropathic pain may have been advantageous, protecting animals after serious injury.
损伤可导致毁灭性的、通常无法治疗的慢性疼痛。尽管急性疼痛感知（伤害感受）在 5 亿多年前就已经进化，但对于慢性疼痛的分子起源几乎一无所知。在这里，我们首次提供证据表明，神经损伤会导致昆虫的慢性神经性敏化。从机制上讲，外周神经损伤会引发中枢抑制丧失，从而驱动逃逸回路可塑性和神经性痛觉过敏。在分子水平上，GABA 能（γ-氨基丁酸）神经元内的兴奋性毒性信号需要乙酰胆碱受体，并导致 GABA 能神经元的 Caspase 依赖性死亡。相反，破坏 GABA 信号足以在没有损伤的情况下引发痛觉过敏。最后，我们确定了保守的转录因子 twist 作为一个关键的下游调节因子，它驱动 GABA 能神经元的死亡和神经性痛觉过敏。总的来说，我们定义了损伤如何导致昆虫的痛觉过敏，并描述了神经性疼痛的原始前体可能是有利的，它可以在严重损伤后保护动物。
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