Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice.
Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice.
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DOI：
10.1523/jneurosci.3859-11.2011
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发表时间：
2011-10-26
期刊：
影响因子：
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通讯作者：
Mogil JS
中科院分区：
文献类型：
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作者：
Sorge RE;LaCroix-Fralish ML;Tuttle AH;Sotocinal SG;Austin JS;Ritchie J;Chanda ML;Graham AC;Topham L;Beggs S;Salter MW;Mogil JS
越来越多的人认识到先天免疫系统在慢性疼痛的调节中起着重要的作用，参与这一过程的一个分子是Toll样受体4(TLR4)。在这里，我们利用药理学和遗传操作发现，用激动剂脂多糖(LPS)激活脊髓中的TLR4会导致强烈的机械性痛觉异常，但只在雄性小鼠中发生。脊髓内毒素对雌性小鼠无致痛作用。TLR4在炎症性疼痛(完全弗氏佐剂)和神经性疼痛(保留神经损伤)中也有性别特异性的作用：男性的疼痛行为依赖于TLR4，而女性的疼痛行为不依赖于TLR4。性别差异似乎仅限于脊髓，因为给大脑或后爪注射脂多糖在两性中都会产生同等的超感痛觉，对疼痛也是特有的，因为鞘内脂多糖在两性中产生同样的低温。TLR4在雄性小鼠疼痛行为中的作用依赖于睾酮，如性腺切除和激素替代所显示的那样。我们发现，在基线或脂多糖后，脊髓TLR4的表达没有性别差异，这表明在不涉及TLR4的雌性小鼠中存在平行的脊髓疼痛处理电路。
The innate immune system is increasingly appreciated to play an important role in the mediation of chronic pain, and one molecule implicated in this process is the Toll-like receptor 4 (TLR4). Here using pharmacological and genetic manipulations we found that activating TLR4 in the spinal cord, with the agonist lipopolysaccharide (LPS), causes robust mechanical allodynia but only in male mice. Spinal LPS had no pain-producing effect in female mice. TLR4 also has a sex-specific role in inflammatory (complete Freund’s adjuvant) and neuropathic (spared nerve injury) pain: pain behaviors were TLR4-dependent in males but TLR4-independent in females. The sex differences appear to be specific to the spinal cord, as LPS administered to the brain or the hindpaw produces equivalent allodynia in both sexes, and specific to pain, as intrathecal LPS produces equivalent hypothermia in both sexes. The involvement of TLR4 in pain behaviors in male mice is dependent on testosterone, as shown by gonadectomy and hormone replacement. We found no sex differences in spinal Tlr4 expression at baseline or after LPS, suggesting the existence of parallel spinal pain processing circuitry in female mice not involving TLR4s.