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首页> 外文期刊>The European Journal of Neuroscience >Estrogen controls PKCepsilon-dependent mechanical hyperalgesia through direct action on nociceptive neurons.
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Estrogen controls PKCepsilon-dependent mechanical hyperalgesia through direct action on nociceptive neurons.

机译：雌激素通过对伤害性神经元的直接作用来控制PKCepsilon依赖的机械性痛觉过敏。

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摘要

Protein kinase C epsilon (PKCepsilon) is an important intracellular signaling molecule in primary afferent nociceptors, implicated in acute and chronic inflammatory as well as neuropathic pain. In behavioral experiments inflammatory mediators produce PKCepsilon-dependent hyperalgesia only in male rats. The mechanism underlying this sexual dimorphism is unknown. We show that the hormone environment of female rats changes the nociceptive signaling in the peripheral sensory neuron. This change is maintained in culture also in the absence of a gender-simulating environment. Stimulation of beta(2)-adrenergic receptors (beta(2)-AR) leads to PKCepsilon activation in cultured dorsal root ganglia (DRG) neurons derived from male but not from female rats. Addition of estrogen to male DRG neurons produces a switch to the female phenotype, namely abrogation of beta(2)-AR-initiated activation of PKCepsilon. Estrogen interferes downstream of the beta(2)-AR with the signaling pathway leading from exchange protein activated by cAMP (Epac) to PKCepsilon. The interfering action is fast indicating a transcriptional-independent mechanism. Estrogen has a dual effect on PKCepsilon. If applied before beta(2)-AR or Epac stimulation, estrogen abrogates the activation of PKCepsilon. In contrast, estrogen applied alone leads to a brief translocation of PKCepsilon. Also in vivo the activity of estrogen depends on the stimulation context. In male rats, intradermal injection of an Epac activator or estrogen alone induces mechanical hyperalgesia through a PKCepsilon-dependent mechanism. In contrast, injection of estrogen preceding the activation of Epac completely abrogates the Epac-induced mechanical hyperalgesia. Our results suggest that gender differences in nociception do not reflect the use of generally different mechanisms. Instead, a common set of signaling pathways can be modulated by hormones.
机译：蛋白激酶C epsilon（PKCepsilon）是原发传入伤害感受器中重要的细胞内信号传导分子，与急性和慢性炎症以及神经性疼痛有关。在行为实验中，炎症介质仅在雄性大鼠中产生PKCepsilon依赖性痛觉过敏。这种性二态性的潜在机制尚不清楚。我们表明雌性大鼠的激素环境改变周围感觉神经元的伤害性信号传导。在没有模仿性别的环境下，这种变化在文化中也得以保持。刺激β（2）-肾上腺素受体（β（2）-AR）导致雄性而非雌性大鼠培养的背根神经节（DRG）神经元中的PKCepsilon激活。雄性DRG神经元中添加雌激素会导致雌性表型转换，即废除beta（2）-AR启动的PKCepsilon激活。雌激素干扰从cAMP（Epac）激活的交换蛋白到PKCepsilon的信号传导途径，干扰β（2）-AR的下游。干扰作用很快，表明转录独立机制。雌激素对PKCepsilon具有双重作用。如果在β（2）-AR或Epac刺激之前使用，雌激素将消除PKCepsilon的激活。相反，单独使用雌激素会导致PKCepsilon短暂移位。同样在体内，雌激素的活性取决于刺激环境。在雄性大鼠中，仅通过皮内注射Epac激活剂或雌激素即可通过PKCepsilon依赖性机制诱导机械性痛觉过敏。相反，在激活Epac之前注射雌激素完全消除了Epac引起的机械性痛觉过敏。我们的研究结果表明，伤害感受中的性别差异并不反映使用普遍不同的机制。取而代之的是，一组常见的信号传导途径可以被激素调节。

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