Estrogen controls PKCε-dependent mechanical hyperalgesia through direct action on nociceptive neurons
Estrogen controls PKCε-dependent mechanical hyperalgesia through direct action on nociceptive neurons
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DOI：
10.1111/j.1460-9568.2006.04913.x
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发表时间：
2006-07-01
影响因子：
3.4
通讯作者：
Levine, Jon D.
中科院分区：
文献类型：
--
作者：
Hucho, Tim B.;Dina, Olayinka A.;Levine, Jon D.
蛋白激酶C β（Protein kinase C β，PKC β）是初级传入伤害感受器中重要的细胞内信号分子，参与急慢性炎性疼痛和神经病理性疼痛。在行为学实验中，炎症介质仅在雄性大鼠中产生PKC ε依赖性痛觉过敏。这种性二态性的机制尚不清楚。我们发现雌性大鼠的激素环境改变了外周感觉神经元的伤害性信号。即使没有模拟性别的环境，这种变化在文化中也得以维持。刺激β（2）-肾上腺素能受体（β（2）-AR）导致培养的雄性大鼠背根神经节（DRG）神经元中PKC β激活，但雌性大鼠没有。向雄性DRG神经元中加入雌激素可使其转变为雌性表型，即消除β（2）-AR启动的PKC β激活。雌激素干扰β（2）-AR下游从cAMP激活的交换蛋白（Epac）到PKC β的信号通路。干扰作用是快速的，表明不依赖于转录的机制。雌激素对PKC ε具有双重影响。如果在β（2）-AR或Epac刺激前应用，雌激素会消除PKC β的激活。相反，单独应用雌激素会导致PKC β的短暂易位。在体内，雌激素的活性也取决于刺激环境。在雄性大鼠中，皮内注射Epac激活剂或雌激素单独通过PKC ε依赖性机制诱导机械性痛觉过敏。相反，在Epac激活之前注射雌激素完全消除Epac诱导的机械性痛觉过敏。我们的研究结果表明，性别差异的伤害性感受并不反映使用一般不同的机制。相反，一组常见的信号通路可以通过激素调节。
Protein kinase C epsilon (PKC epsilon) 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 PKC epsilon-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 PKC epsilon 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 PKC epsilon. Estrogen interferes downstream of the beta(2)-AR with the signaling pathway leading from exchange protein activated by cAMP (Epac) to PKC epsilon. The interfering action is fast indicating a transcriptional-independent mechanism. Estrogen has a dual effect on PKC epsilon. If applied before beta(2)-AR or Epac stimulation, estrogen abrogates the activation of PKC epsilon. In contrast, estrogen applied alone leads to a brief translocation of PKC epsilon. 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 PKC epsilon-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.