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，在关于这个主题的初步研究中，我们评估了雌二醇对三叉神经元基因表达的长期影响。结果构成了一个意想不到的发现，雌二醇上调催乳素（PRL）超过40倍的感觉神经元。后续研究表明，PRL和PRL受体（PRL-R）在雌性和雄性大鼠的感觉神经元中表达，并且辣椒素的应用引起三叉神经感觉神经元的PRL释放。此外，外源性PRL的应用显着和急性增加伤害感受器对辣椒素的反应，如通过内向电流，CGRP胞吐，细胞内钙水平的积累，和伤害反应行为。这些初步的数据提供了强有力的初步支持一个全新的假说，伤害感受器调节的自分泌/旁分泌系统含有PRL。基于这一假设，催乳素可能作为一种新的痛觉过敏剂在女性和男性。我们认为，这一发现具有重大的科学和医学意义，从概念的角度来看是高度创新的。因此，本项目将表征机制介导催乳素的影响，在女性和男性大鼠，并将直接测试的假设，催乳素引起快速增加的反应性感觉神经元的伤害性刺激，如辣椒素。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。具体目标二：确定PRL快速增加三叉神经元对有害化学和热刺激的反应性的机制。具体目标3：表征在体外培养的三叉神经感觉神经元和急性分离和灌流的外周末梢中引起PRL释放的刺激。三叉神经感觉神经元表达PRL和PRLR，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伤害性刺激（如辣椒素）敏感的发现，为伤害感受器通过自分泌/旁分泌PRL系统调节的全新且创新的假说提供了强有力的初步支持，并且阻断PRL-R的化合物可用作性别依赖性疼痛中的新型镇痛药物。

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.