Ectopic endometrium-derived leptin produces estrogen-dependent chronic pain in a rat model of endometriosis.
Ectopic endometrium-derived leptin produces estrogen-dependent chronic pain in a rat model of endometriosis.
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DOI：
10.1016/j.neuroscience.2013.11.008
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发表时间：
2014-01-31
期刊：
影响因子：
3.3
通讯作者：
Levine JD
中科院分区：
文献类型：
--
作者：
Alvarez P;Bogen O;Chen X;Giudice LC;Levine JD
子宫内膜异位症疼痛是一种非常常见且极度致残的疾病，其机制尚不清楚。虽然在子宫内膜异位症患者中有瘦素水平升高的报道，但它们对子宫内膜异位症疼痛的影响尚未得到探讨。使用啮齿类动物子宫内膜异位症模型，我们为瘦素在子宫内膜异位症引起的疼痛中雌激素依赖的贡献提供了证据。在腓肠肌上植入自体子宫组织的大鼠出现子宫内膜异位症样病变和局部慢性疼痛。与异位子宫组织相比，瘦素mRNA和蛋白在子宫内膜异位症样病变中表达上调。重组瘦素肌内注射产生剂量依赖性局部机械性痛觉过敏和伤害感受器对机械刺激的致敏。在瘦素注射后1和24小时，与17β-雌二醇替代治疗的大鼠相比，载体治疗的大鼠卵巢切除术减轻了重组瘦素引起的机械痛觉过敏。最后，病灶内注射聚乙二醇化瘦素受体（Ob-R）拮抗剂或Janus激酶2的抑制剂（它能传导瘦素受体Ob-R信号），显著减轻了子宫内膜异位症模型中的疼痛。综上所述，这些数据支持了一种假说，即异位子宫内膜病变中产生的瘦素通过作用于支配病变的伤害感受器而产生机械性痛觉过敏。这种对瘦素的敏感性取决于雌激素水平。因此，针对瘦素信号的干预，特别是与降低雌激素水平的干预相结合，可能对治疗子宫内膜异位症疼痛有用。
Endometriosis pain is a very common and extremely disabling condition whose mechanism is still poorly understood. While increased levels of leptin have been reported in patients with endometriosis, their contribution to endometriosis pain has not been explored. Using a rodent model of endometriosis we provide evidence for an estrogen-dependent contribution of leptin in endometriosis-induced pain. Rats implanted with autologous uterine tissue onto the gastrocnemius muscle developed endometriosis-like lesions and local chronic pain. Compared to eutopic uterine tissue, leptin mRNA and protein were up-regulated in the endometriosis-like lesions. Intramuscular injection of recombinant leptin in naive rats produced dose-dependent local mechanical hyperalgesia and nociceptor sensitization to mechanical stimulation. Ovariectomy attenuated the mechanical hyperalgesia induced by recombinant leptin, in rats treated with vehicle compared to those treated with 17β-estradiol replacement, at 1 and 24 h after leptin injection. Finally, intralesional injections of a pegylated leptin receptor (Ob-R) antagonist or of an inhibitor of Janus kinase2, which transduces the Ob-R signal of leptin receptor, markedly attenuated pain in the endometriosis model. Taken together these data support the hypothesis that leptin, generated in ectopic endometrial lesions produces mechanical hyperalgesia by acting on nociceptors innervating the lesion. This sensitivity to leptin is dependent on estrogen levels. Thus, interventions targeting leptin signaling, especially in combination with interventions that lower estrogen levels, might be useful for the treatment of endometriosis pain.