Estrogen Receptors and Nociceptive Signaling in Primary Afferent Neurons

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疾病的合并症接近40%至60%。与这些“功能性”疾病相关的发作性或持续性内脏疼痛在女性中的发生率是男性的2 - 3倍。对这一现象的一种可能解释是雌激素对疼痛传递的调节。虽然这种调节的中心部位之前已经被发现，但在这里，我们建议研究一个外围部位，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[Ca2+]流，这是一种假定的伤害性信号。相反，E2也会减弱抗伤害性细胞对阿片受体（MOP）激动剂的反应，这意味着E2可能会增强细胞对伤害性信号的反应。

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.