Immature spinal cord neurons are dynamic regulators of adult nociceptive sensitivity.
Immature spinal cord neurons are dynamic regulators of adult nociceptive sensitivity.
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DOI：
10.1111/jcmm.12648
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发表时间：
2015-10
影响因子：
5.3
通讯作者：
Mao J
中科院分区：
文献类型：
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作者：
Rusanescu G;Mao J
慢性疼痛是一种使人衰弱的疾病，其机制尚不清楚。伤害感受敏感性可能受遗传因素调节，其中一些已分别与神经元祖细胞和神经元分化有关。这表明干扰神经元分化的遗传因素可能通过延长脊髓神经元的不成熟、过度兴奋阶段而导致伤害敏感性的慢性增加。虽然成年啮齿类动物脊髓神经发生以前被证明，这些祖细胞的命运是未知的。在这里，我们表明，周围神经损伤诱导广泛的脊髓神经发生和长期增加的脊髓板层I-II神经元损伤同侧的数量。这些新神经元的产生和成熟与伤害性行为的时程和调制相关，并且短暂地模仿慢性疼痛的遗传修饰动物模型中存在的细胞和行为条件。这表明，在任何时候，脊髓背角中存在的未成熟神经元的数量有助于调节伤害性敏感性。这些神经元的持续更新，可以在正常和受损状态之间波动，是伤害感受敏感性的动态调节器。为了支持这一假设，我们发现，神经元分化的促进剂抑制，而神经发生的促进剂增加长期的伤害感受。TrkB激动剂，众所周知的短期伤害感受促进剂，通过促进新产生的未成熟神经元的分化来显著抑制长期伤害感受。这些发现表明，神经元分化的促进剂可用于缓解慢性疼痛。
Chronic pain is a debilitating condition with unknown mechanism. Nociceptive sensitivity may be regulated by genetic factors, some of which have been separately linked to neuronal progenitor cells and neuronal differentiation. This suggests that genetic factors that interfere with neuronal differentiation may contribute to a chronic increase in nociceptive sensitivity, by extending the immature, hyperexcitable stage of spinal cord neurons. Although adult rodent spinal cord neurogenesis was previously demonstrated, the fate of these progenitor cells is unknown. Here, we show that peripheral nerve injury in adult rats induces extensive spinal cord neurogenesis and a long-term increase in the number of spinal cord laminae I–II neurons ipsilateral to injury. The production and maturation of these new neurons correlates with the time course and modulation of nociceptive behaviour, and transiently mimics the cellular and behavioural conditions present in genetically modified animal models of chronic pain. This suggests that the number of immature neurons present at any time in the spinal cord dorsal horns contributes to the regulation of nociceptive sensitivity. The continuous turnover of these neurons, which can fluctuate between normal and injured states, is a dynamic regulator of nociceptive sensitivity. In support of this hypothesis, we find that promoters of neuronal differentiation inhibit, while promoters of neurogenesis increase long-term nociception. TrkB agonists, well-known promoters of nociception in the short-term, significantly inhibit long-term nociception by promoting the differentiation of newly produced immature neurons. These findings suggest that promoters of neuronal differentiation may be used to alleviate chronic pain.