Neuropathic Pain Is Constitutively Suppressed in Early Life by Anti-Inflammatory Neuroimmune Regulation
Neuropathic Pain Is Constitutively Suppressed in Early Life by Anti-Inflammatory Neuroimmune Regulation
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DOI：
10.1523/jneurosci.2315-14.2015
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发表时间：
2015-01-14
影响因子：
5.3
通讯作者：
Fitzgerald, Maria
中科院分区：
文献类型：
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作者：
McKelvey, Rebecca;Berta, Temugin;Fitzgerald, Maria
周围神经损伤可引起成人神经性疼痛，但不会引起婴儿；事实上，由于未知的原因，青春期前的神经性疼痛很少见。我们在这里表明，幼龄雄性大鼠和小鼠在神经损伤后缺乏神经性疼痛反应是由于对背角疼痛活动的积极的、构成性免疫抑制。与成人神经损伤在脊髓背角触发促炎免疫反应相反，婴儿神经损伤触发抗炎免疫反应，其特征是IL-4和IL-10显著增加。这种即时的抗炎反应也可以通过直接刺激幼鼠的c -纤维神经来引起，而不是成年小鼠。鞘内抗il10阻断抗炎活性揭示了幼龄神经损伤小鼠的神经性疼痛行为，表明幼龄小鼠的疼痛超敏反应受到显性抗炎神经免疫反应的积极抑制。随着幼年神经损伤小鼠进入青春期（出生后25-30天），其背角免疫反应从抗炎转变为促炎反应，其特征是TNF和BDNF显著增加，这伴随着晚发性神经性疼痛行为和背角细胞对皮肤机械和冷刺激的敏感性增加。这些发现表明，早期神经损伤后的神经性疼痛并非不存在，而是受到神经免疫活动的抑制，并且当神经免疫谱发生变化时，“潜伏”疼痛仍然可以在青春期出现。这些数据可以解释为什么神经性疼痛在幼儿中很少见，也可以解释为什么青少年患者会无缘无故地出现神经性疼痛。
Peripheral nerve injury can trigger neuropathic pain in adults but not in infants; indeed, for unknown reasons, neuropathic pain is rare before adolescence. We show here that the absence of neuropathic pain response in infant male rats and mice following nerve injury is due to an active, constitutive immune suppression of dorsal horn pain activity. In contrast to adult nerve injury, which triggers a proinflammatory immune response in the spinal dorsal horn, infant nerve injury triggers an anti-inflammatory immune response, characterized by significant increases in IL-4 and IL-10. This immediate anti-inflammatory response can also be evoked by direct C-fiber nerve stimulation in infant, but not adult, mice. Blockade of the anti-inflammatory activity with intrathecal anti-IL10 unmasks neuropathic pain behavior in infant nerve injured mice, showing that pain hypersensitivity in young mice is actively suppressed by a dominant anti-inflammatory neuroimmune response. As infant nerve injured mice reach adolescence (postnatal day 25-30), the dorsal horn immune profile switches from an anti-inflammatory to a proinflammatory response characterized by significant increases in TNF and BDNF, and this is accompanied by a late onset neuropathic pain behavior and increased dorsal horn cell sensitivity to cutaneous mechanical and cold stimuli. These findings show that neuropathic pain following early life nerve injury is not absent but suppressed by neuroimmune activity and that "latent" pain can still emerge at adolescence, when the neuroimmune profile changes. The data may explain why neuropathic pain is rare in young children and also why it can emerge, for no observable reason, in adolescent patients.