Impact of Early Experience on Vulvovaginal Sensitivity in Adult Mouse

项目总结（见说明）： 早期经验已被证明对慢性疼痛的患病率有深远的影响，特别是在内脏感觉系统内。早产儿暴露于许多应激源，包括反复的侵入性手术（通常没有充分的麻醉）和长时间的母亲分离。由母体分离或不可预测的休克产生的大鼠新生儿应激模型产生内脏痛觉过敏，新生大鼠在生命的第二周期间接受结肠或膀胱的有害机械或化学刺激也是如此。本提案的重点是确定新生儿应激或刺激如何影响成年小鼠外阴和阴道的伤害性处理，以及是否消融选择的感觉神经元群体可以使外阴阴道感觉正常化。外阴疼痛在临床上被定义为外阴的慢性不适或疼痛，通常在没有特定病理或神经障碍的情况下以烧灼感、刺痛或疼痛发生。尽管估计有15%的女性经历持续至少3个月的慢性或诱发性外阴阴道疼痛，但相对较少的已发表研究调查了外阴阴道神经支配的变化，目前文献中也没有动物模型。本申请中的实验概述于两个特定目的，其设计为1）确定新生儿应激或刺激如何影响外阴阴道敏感性和支配受影响组织的感觉神经元的伤害感受表型，和2）采用生长因子缀合的皂草素选择性地沉默负责疼痛感觉的那些纤维，作为治疗人类外阴痛的临床前试验。这些研究的成功完成不仅将提供第一个公开发表的外阴痛模型，而且也是开发一类新化合物的第一步，这种化合物可以减轻慢性盆腔疼痛而不影响正常感觉。考虑到外阴痛和其他慢性盆腔疼痛综合征（例如子宫内膜异位症、肠易激综合征和间质性膀胱炎）之间的高度共病性，化学消融该伤害感受器群体也可以减轻这些综合征的症状，

PROJECT SUMMARY (See instructions): Early experience has been shown to have a profound impact on the prevalence of chronic pain, particularly within the viscerosensory system. Preterm neonates are exposed to numerous stressors, including repeated invasive procedures (often without adequate anesthesia) and prolonged periods of maternal separation. Models of neonatal stress in rats, generated by either maternal separation or unpredictable shock, produce visceral hyperalgesia, as do neonatal rats that receive noxious mechanical or chemical irritation of the colon or bladder during the second week of life. The focus of this proposal is to determine how neonatal stress or irritation affects nociceptive processing from the vulva and vagina of adult mice and whether ablation of a select population of sensory neurons can normalize vulvovaginal sensation. Vulvodynia is clinically defined as chronic discomfort or pain of the vulva, often occurring as burning, stinging or soreness, in the absence of specific pathology or neurological disorder. Despite an estimated 15% of women experiencing chronic or evoked vulvovaginal pain lasting at least 3 months, relatively few published studies have investigated changes in vulvovaginal innervation and no animal models exist in the current literature. The experiments in this application are outlined in two specific aims designed to 1) determine how neonatal stress or irritation impacts vulvovaginal sensitivity and the nociceptive phenotype of sensory neurons innervating the affected tissue and 2) employ growth factor-conjugated saporin to selectively silence those fibers responsible for pain sensations as a preclinical test for treating vulvodynia in humans. Successful completion of these studies will not only provide the first published model of vulvodynia, but is also the first step in developing a new class of compounds that alleviates chronic pelvic pain without affecting normal sensations. Considering the high degree of comorbidity between vulvodynia and other chronic pelvic pain syndromes, e.g. endometriosis, irritable bowel syndrome and interstitial cystitis, chemical ablation of this population of nociceptors could also alleviate symptoms of these syndromes, as well