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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Leptin derived from adipocytes in injured peripheral nerves facilitates development of neuropathic pain via macrophage stimulation
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Leptin derived from adipocytes in injured peripheral nerves facilitates development of neuropathic pain via macrophage stimulation

机译：源自受损外周神经中脂肪细胞的瘦素通过巨噬细胞刺激促进神经性疼痛的发展

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摘要

Nerve injury may result in neuropathic pain, characterized by allodynia and hyperalgesia. Accumulating evidence suggests the existence of a molecular substrate for neuropathic pain produced by neurons, glia, and immune cells. Here, we show that leptin, an adipokine exclusively produced by adipocytes, is critical for the development of tactile allodynia through macrophage activation in mice with partial sciatic nerve ligation (PSL). PSL increased leptin expression in adipocytes distributed at the epineurium of the injured sciatic nerve (SCN). Leptin-deficient animals, ob/ob mice, showed an absence of PSL-induced tactile allodynia, which was reversed by the administration of leptin to the injured SCN. Perineural injection of a neutralizing antibody against leptin reproduced this attenuation. Macrophages recruited to the peri-neurium of the SCN expressed the leptin receptor and phosphor-ylated signal transducer and activator of transcription 3 (pSTAT3), a transcription factor downstream of leptin. PSL also up-regulated the accepted mediators of neuropathic pain-namely, cyclooxy-genase-2, inducible nitric oxide synthase, and matrix metal-loprotease-9-in the injured SCN, with transcriptional activation of their gene promoters by pSTAT3. This up-regulation was partly reproduced in a macrophage cell line treated with leptin. Administration of peritoneal macrophages treated with leptin to the injured SCN reversed the failure of ob/ob mice to develop PSL-induced tactile allodynia. We suggest that leptin.induces recruited macrophages to produce pronociceptive mediators for the development of tactile allodynia. This report shows that adipocytes associated with primary afferent neurons may be involved in the development of neuropathic pain through adipokine secretion.
机译：神经损伤可能导致神经性疼痛，其特征是异常性疼痛和痛觉过敏。越来越多的证据表明，存在由神经元，神经胶质细胞和免疫细胞产生的神经性疼痛的分子底物。在这里，我们显示出瘦素（一种由脂肪细胞专门产生的脂肪因子）对于通过部分坐骨神经结扎（PSL）的小鼠中的巨噬细胞激活对触觉性异常性疼痛的发展至关重要。 PSL增加了受损坐骨神经（SCN）的神经外膜分布的脂肪细胞中瘦素的表达。缺乏瘦素的动物（ob / ob小鼠）显示不存在PSL诱导的触觉异常性疼痛，通过向受伤的SCN施用瘦素可以逆转这种异常。鞘膜内注射针对瘦蛋白的中和抗体再现了这种衰减。募集到SCN神经周围的巨噬细胞表达了瘦素受体，磷酸化的信号转导子和转录激活因子3（pSTAT3），这是瘦素下游的转录因子。 PSL还上调了受损SCN中神经性疼痛的公认介导因子，即环氧合酶2，诱导型一氧化氮合酶和基质金属蛋白酶9，并通过pSTAT3激活了它们的基因启动子。这种上调在用瘦素处理的巨噬细胞系中部分复制。将瘦蛋白处理的腹膜巨噬细胞给予受损的SCN可逆转ob / ob小鼠发展为PSL诱导的触觉异常性疼痛的失败。我们建议瘦素诱导募集的巨噬细胞产生触觉性异常性疼痛的触觉感受器。该报告表明，与原发传入神经元相关的脂肪细胞可能通过脂肪因子的分泌参与神经性疼痛的发展。

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  • 作者

    Takehiko Maeda; Norikazu Kiguchi; Yuka Kobayashi; Toshihiko lkuta; Masanobu Ozaki; Shiroh Kishioka;

  • 作者单位

    Department of Pharmacology, Wakayama Medical University, Wakayama 641-0012, Japan;

    Department of Pharmacology, Wakayama Medical University, Wakayama 641-0012, Japan;

    Department of Pharmacology, Wakayama Medical University, Wakayama 641-0012, Japan;

    Department of Pharmacology, Wakayama Medical University, Wakayama 641-0012, Japan;

    Department of Toxicology, Niigata University of Pharmacy and Applied Life Science, Niigata 950-2028, Japan;

    Department of Pharmacology, Wakayama Medical University, Wakayama 641-0012, Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    adipokine; allodynia; C/EBP; fat; STAT;

    机译：脂肪因子异常性疼痛C / EBP;脂肪;统计;

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