Estrogen Receptors and Nociceptive Signaling in Primary Afferent Neurons

描述（由申请人提供）：临床研究表明，功能性疼痛综合征（如肠易激综合征（IBS）、纤维肌痛、慢性盆腔疼痛和躯体形式障碍）的共病率接近40%至60%。与这些“功能性”疾病相关的间歇性或持续性内脏痛的发生率，女性比男性高2 - 3倍。这种现象的一个可能的解释是疼痛传递的雌激素调节。虽然这种调制的中央网站已经显示以前，在这里，我们建议研究外周网站，背根神经节（DRG）。在DRG神经元中，17 <$-雌二醇（E2）迅速抑制ATP诱导的细胞内钙[Ca 2 +]流，ATP是一种假定的伤害性信号。相反，E2也减弱对阿片受体（MOP）激动剂的抗伤害性细胞反应，这意味着E2可能增强对伤害性信号的细胞反应。 这项提案，雌激素受体介导的初级感觉神经元在雌性小鼠的伤害性信号，将测试一个一般的假设，即E2作用于初级传入伤害感受器具有亲伤害性和抗伤害性的影响，这取决于哪些信号收敛于DRG。首先，将在野生型、雌激素受体-α和雌激素受体-β敲除小鼠中研究不同雌激素受体（ER）在嘌呤能（P2 X）和香草素（TRPV 1）受体的E2活化中的作用。其次，由于我们假设E2可能对内脏伤害感受器和皮肤伤害感受器的作用不同，我们将比较来自敲除小鼠和野生型小鼠的逆行标记内脏和皮肤DRG神经元中的[Ca 2 +]i对P2 X和TRPV 1受体激活的反应。第三，E2可能通过干扰MOP而负性调节阿片镇痛。药理学操作将用于确定ER激活如何调节Ca 2+通道和MOP功能。受体结合将决定E2是否改变DRG中MOP的数量和亲和力以及MOP与G蛋白偶联的位点特异性调节。这些实验将共同定义E2调节伤害性信号传导的新位点和机制。此外，他们将提供重要的信息E2对初级感觉神经元的作用，以更好地了解功能性疼痛相关综合征的临床表现中观察到的性别差异。 伤害感受系统与功能性疾病的病因学有关，这些功能性疾病往往并发抑郁症、恐慌症和其他精神疾病，所有这些都构成健康风险。设计新的性别特异性疗法将对功能性疼痛障碍患者的健康相关生活质量产生重大影响，显著减少治疗干预。

DESCRIPTION (provided by applicant): Clinical studies suggest the co-morbidity of functional pain syndromes such as irritable bowel syndrome (IBS), fibromyalgia, chronic pelvic pain and somatoform disorders approaches 40% to 60%. The incidence of episodic or persistent visceral pain associated with these "functional" disorders is two to three times higher in women than in men. One of the possible explanations for this phenomenon is the estrogen modulation of pain transmission. While a central site of this modulation has been shown previously, here we propose to study a peripheral site, the dorsal root ganglion (DRG). In DRG neurons, 17¿-estradiol (E2) rapidly inhibits intracellular calcium [Ca2+] flux induced by ATP, a putative nociceptive signal. Conversely, E2 also attenuates anti-nociceptive cellular responses to a ¿-opioid receptor (MOP) agonist, implying that E2 may enhance cellular responses to nociceptive signals. This proposal, Estrogen Receptors Mediate Nociceptive Signaling in Primary Sensory Neurons in Female Mice, will test a general hypothesis that E2 acting on primary afferent nociceptors has both pro-nociceptive and anti-nociceptive effects depending on which signals converge upon DRG. First, the role of different estrogen receptors (ER) in E2 activation of purinergic (P2X) and vanilloid (TRPV1) receptors will be studied in wild type, estrogen receptor-a and estrogen receptor-¿ knock-out mice. Second, since we hypothesize that E2 may act differently on visceral then on cutaneous nociceptors, we will compare the [Ca2+]i response to activation of P2X and TRPV1 receptors in retrograde-labeled visceral and cutaneous DRG neurons from knock-out and wild type mice. Third, E2 may negatively modulate opioid analgesia by interfering with MOP. Pharmacological manipulations will be used to determine how ER activation modulates Ca2+ channel and MOP functions. Receptor binding will determine if E2 alters the number and affinity of MOP in the DRG and the site-specific regulation of MOP coupling to G-proteins. Together these experiments will define a new site(s) and mechanism of E2 modulation of nociceptive signaling. Furthermore, they will provide important information about the action of E2 on primary sensory neurons for a better understanding of gender differences observed in the clinical presentation of functional pain-associated syndromes. Nociceptive systems are implicated in the etiology of functional disorders, which often are complicated by co-morbid depression, panic and other psychiatric disorders, all pose health risks. Designing new gender-specific therapies will have a major impact on health-related quality of life in patients with functional pain disorders, significantly reducing therapeutic interventions.