Prolactin Regulation of Trigeminal Nociceptors

描述（由申请人提供）：性别和疼痛的作用仍然是一个主要的卫生保健问题，在这一主题的初步研究中，我们评估了雌二醇对三叉神经细胞基因表达的长期影响。结果发现，雌二醇可使感觉神经元中的催乳素（PRL）上调40倍以上。后续研究表明，PRL和PRL受体（PRL- r）在雌雄大鼠的感觉神经元中均有表达，辣椒素的应用可引起三叉神经感觉神经元中PRL的释放。此外，外源性PRL的应用显著和急剧增加伤害感受器对辣椒素的反应，通过向内电流、CGRP胞外分泌、细胞内钙水平的积累和伤害行为来测量。这些初步数据为包含PRL的自分泌/旁分泌系统调节伤害感受器的全新假设提供了强有力的初步支持。基于这一假设，PRL可能在女性和男性中都是一种新的痛觉过敏剂。我们相信这一发现具有重大的科学和医学意义，并且从概念的角度来看是高度创新的。因此，本项目将描述雌性和雄性大鼠中调节催乳素作用的机制，并将直接验证PRL引起感觉神经元对辣椒素等有害刺激的反应性快速增加的假设。我们的具体目标是：具体目标1：确定外源性PRL对辣椒素和炎症诱导的痛觉过敏/异常性疼痛的影响。具体目标2：确定PRL快速增加三叉神经对有害化学和热刺激的反应性的机制。特异性目标3：表征体外培养和急性分离和过度使用的外周末梢诱导三叉感觉神经元释放PRL的刺激。三叉神经感觉神经元同时表达PRL和PRLR的发现，以及外源性PRL的应用显著且快速地使三叉神经伤害感受器对辣椒素等有害刺激敏感的发现，为自分泌/旁分泌PRL系统调节伤害感受器的全新创新假设提供了强有力的初步支持，并且阻断PRL- r的化合物可能作为一类新型的镇痛药物用于性别依赖性疼痛。

DESCRIPTION (provided by applicant): The role of gender and pain remains a major health care problem, and in preliminary studies on this topic, we evaluated the long-term effects of estradiol on gene expression in trigeminal neurons. The results constituted an unexpected discovery that estradiol upregulates prolactin (PRL) more than 40 fold in sensory neurons. Follow-up studies demonstrated that PRL and the PRL receptors (PRL-R) are expressed in sensory neurons of both female and male rats, and that application of capsaicin evokes PRL release from trigeminal sensory neurons. Furthermore, application of exogenous PRL significantly and acutely increases nociceptor responsiveness to capsaicin as measured by inward currents, CGRP exocytosis, accumulation of intracellular calcium levels, and nocifensive behavior. These preliminary data provide strong initial support for a completely new hypothesis of nociceptor regulation by an autocrine/paracrine system containing PRL. Based upon this hypothesis, PRL may serve as a novel hyperalgesic agent in both females and in males. We believe that this discovery has substantial scientific and medical implications, and is highly innovative from a conceptual perspective. Therefore, this project will characterize the mechanisms mediating prolactin effects in female and male rats and will directly test the hypotheses that PRL evokes a rapid increase in the responsiveness sensory neurons to noxious stimuli such as capsaicin. Our specific aims will: Specific Aim 1: Determine the effects of exogenous PRL on capsaicin- and inflammation-induced hyperalgesia/allodynia. Specific Aim 2: Determine the mechanisms by which PRL rapidly increases the responsiveness of trigeminal neurons to noxious chemical and thermal stimuli. Specific Aim 3: Characterize the stimuli that evoke PRL release in trigeminal sensory neurons from in vitro cultures and from acutely isolated and superfused peripheral terminals. The discovery that trigeminal sensory neurons express both PRL and PRLR, and that application of exogenous PRL significantly and rapidly sensitizes trigeminal nociceptors to noxious stimuli such as capsaicin, provides strong initial support for a completely new and innovative hypothesis of nociceptor regulation by an autocrine/paracrine PRL system, and compounds that block the PRL-R may serve as a novel class of analgesic drugs in gender dependent pain.