Marked Sexual Dimorphism in the Role of the Ryanodine Receptor in a Model of Pain Chronification in the Rat
Marked Sexual Dimorphism in the Role of the Ryanodine Receptor in a Model of Pain Chronification in the Rat
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DOI：
10.1038/srep31221
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发表时间：
2016-08-08
影响因子：
4.6
通讯作者：
Levine, Jon D.
中科院分区：
文献类型：
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作者：
Ferrari, Luiz F.;Khomula, Eugen V.;Levine, Jon D.
痛觉过敏启动是一种向慢性疼痛转变的雌激素依赖性模型，由激活蛋白激酶 C epsilon (PKC epsilon) 的受体激动剂产生，发生在雄性大鼠中，但不会发生在雌性大鼠中。然而，PKC epsilon 下游第二信使（例如兰尼碱受体）的激活会诱导两性的启动。由于雌激素调节细胞内钙，我们研究了雌激素和兰尼定之间的相互作用对女性发生启动的易感性。能够在雌性中诱导启动的兰尼碱最低剂量（1 pg）是雄性所需剂量（100 ng）的 1/100,000，这种作用依赖于兰尼碱受体的激活。用雌激素受体 α (ER α) 反义而非 β (ER β) mRNA 治疗雌性大鼠，可阻止低剂量兰尼定诱导引发，而 ER α 激动剂 PPT 则诱导兰尼定受体依赖性引发。在体外，将低浓度（2 nM）的兰尼碱应用于雌性培养的小 DRG 神经元，可显着增强咖啡因诱导的兰尼碱受体释放的钙。这种效应仅在存在 β-雌二醇或 PPT 的情况下培养的 IB4+ 神经元中观察到。我们的结果证明 ERa 在兰尼定受体依赖性向慢性疼痛的转变中具有深远的调节作用。
Hyperalgesic priming, an estrogen dependent model of the transition to chronic pain, produced by agonists at receptors that activate protein kinase C epsilon (PKC epsilon), occurs in male but not in female rats. However, activation of second messengers downstream of PKC epsilon, such as the ryanodine receptor, induces priming in both sexes. Since estrogen regulates intracellular calcium, we investigated the interaction between estrogen and ryanodine in the susceptibility to develop priming in females. The lowest dose of ryanodine able to induce priming in females (1 pg) is 1/100,000th that needed in males (100 ng), an effect dependent on the activation of ryanodine receptors. Treatment of female rats with antisense to estrogen receptor alpha (ER alpha), but not beta (ER beta), mRNA, prevented the induction of priming by low dose ryanodine, and the ER alpha agonist, PPT, induced ryanodine receptor-dependent priming. In vitro application of ryanodine in low concentration (2 nM) to small DRG neurons cultured from females, significantly potentiated calcium release via ryanodine receptors induced by caffeine. This effect was only observed in IB4+ neurons, cultured in the presence of beta-estradiol or PPT. Our results demonstrate a profound regulatory role of ERa in ryanodine receptor-dependent transition to chronic pain.