McKelvey Rebecca, Berta Temugin, Old Elizabeth, Ji Ru-Rong, Fitzgerald Maria
Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom.
Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, and.
J Neurosci. 2015 Jan 14;35(2):457-66. doi: 10.1523/JNEUROSCI.2315-14.2015.
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.
周围神经损伤会在成年人中引发神经性疼痛，但在婴儿中却不会；事实上，出于未知原因，神经性疼痛在青春期前很少见。我们在此表明，雄性幼鼠和小鼠在神经损伤后没有神经性疼痛反应，是由于背角疼痛活动受到主动的、组成性的免疫抑制。与成年神经损伤引发脊髓背角促炎免疫反应不同，幼体神经损伤引发抗炎免疫反应，其特征是白细胞介素-4和白细胞介素-10显著增加。这种即时抗炎反应也可通过直接刺激幼体（而非成年）小鼠的C纤维神经诱发。用鞘内注射抗白细胞介素-10阻断抗炎活性，会使幼体神经损伤小鼠出现神经性疼痛行为，表明幼鼠的疼痛超敏反应被占主导的抗炎神经免疫反应积极抑制。当幼体神经损伤小鼠进入青春期（出生后第25 - 30天）时，背角免疫特征从抗炎反应转变为促炎反应，其特征是肿瘤坏死因子和脑源性神经营养因子显著增加，同时伴有迟发性神经性疼痛行为以及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，早期生活神经损伤后的神经性疼痛并非不存在，而是被神经免疫活动抑制，并且当神经免疫特征发生变化时，“潜伏”的疼痛在青春期仍可能出现。这些数据可能解释了为什么神经性疼痛在幼儿中很少见，以及为什么在青少年患者中它会毫无明显原因地出现。
