Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143, USA.
Sci Rep. 2016 Aug 8;6:31221. doi: 10.1038/srep31221.
Hyperalgesic priming, an estrogen dependent model of the transition to chronic pain, produced by agonists at receptors that activate protein kinase C epsilon (PKCε), occurs in male but not in female rats. However, activation of second messengers downstream of PKCε, 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 1/100,000(th) 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 (ERα), but not beta (ERβ), mRNA, prevented the induction of priming by low dose ryanodine, and the ERα 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 β-estradiol or PPT. Our results demonstrate a profound regulatory role of ERα in ryanodine receptor-dependent transition to chronic pain.
超敏性引发，一种依赖于雌激素的慢性疼痛转变模型，由激活蛋白激酶 C epsilon (PKCε) 受体的激动剂产生，仅发生在雄性大鼠中，而不在雌性大鼠中。然而，PKCε下游第二信使的激活，如肌质网钙释放通道（ryanodine receptor），会在两性中诱导引发。由于雌激素调节细胞内钙，我们研究了雌激素与肌质网钙在雌性动物引发敏感性中的相互作用。能够在雌性动物中诱导引发的最低剂量的肌质网钙（1 pg）是在雄性动物中所需剂量的 1/100,000（千分之一）（100 ng），这是一种依赖于肌质网钙释放通道激活的效应。用雌激素受体 α (ERα) 反义寡核苷酸而非β (ERβ) 治疗雌性大鼠，mRNA 可防止低剂量肌质网钙诱导的引发，并且 ERα 激动剂 PPT 诱导了肌质网钙释放通道依赖性引发。在体外，将低浓度（2 nM）的肌质网钙应用于从小鼠背根神经节（DRG）培养的神经元中，可显著增强咖啡因诱导的肌质网钙释放。仅在存在β-雌二醇或 PPT 的情况下，IB4+神经元中观察到这种作用。我们的结果表明，ERα 在肌质网钙释放通道依赖性慢性疼痛转变中具有深远的调节作用。
