Prolactin Regulation of Trigeminal Nociceptors

描述(申请人提供)：性别和疼痛的作用仍然是一个主要的医疗保健问题，在这个主题的初步研究中，我们评估了雌二醇对三叉神经细胞基因表达的长期影响。这一结果构成了一个意想不到的发现，即雌二醇上调感觉神经元中催乳素(PRL)的水平超过40倍。后续研究表明，PRL及其受体(PRL-R)在雌性和雄性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释放PRL。此外，外源性PRL的应用显著和急剧地增加了伤害性感受器对辣椒素的反应，通过内向电流、CGRP胞吐、细胞内钙水平的积累和伤害行为来衡量。这些初步数据为一种全新的假设提供了强有力的初步支持，即含有催乳素的自分泌/旁分泌系统对伤害性感受器的调控。根据这一假说，催乳素可能是一种新型的女性和男性痛觉过敏药物。我们相信，这一发现具有重大的科学和医学意义，从概念的角度来看，具有很高的创新性。因此，本项目将表征雌性和雄性大鼠催乳素效应的调节机制，并将直接检验PRL引起感觉神经元对辣椒素等伤害性刺激的反应性迅速增加的假设。我们的具体目标将：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/超敏的影响。具体目标2：确定催乳素快速增加三叉神经细胞对化学和热伤害性刺激反应的机制。具体目标3：从体外培养和急性分离和超融合的外周终末鉴定三叉神经感觉神经元释放催乳素的刺激。三叉神经感觉神经元同时表达PRL和PRLR，外源性PRL的应用显著和快速地使三叉神经痛感受器对辣椒素等伤害性刺激敏感，这一发现为自分泌/旁分泌PRL系统调节伤害性感受器这一全新的创新假说提供了强有力的初步支持，阻断PRL-R的化合物可能成为一类治疗性别依赖性疼痛的新型止痛药物。

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.