SEX SPECIFIC GENETIC MEDIATION OF PAIN AND ANALGESIA

疼痛是一个巨大的人类健康问题， 发病率，甚至直接导致死亡率。 临床疼痛 这些疾病的发生频率存在明显的性别差异， 严重性。 对这些差异的一种可能解释是， 性别对疼痛的敏感性可能不同。 事实上，当差异 许多种类的雌性动物，包括啮齿类动物， 对疼痛更敏感，更不耐痛。 敏感度越高 女性对疼痛的反应伴随着对镇痛剂的敏感性降低 吗啡等药物。 有证据表明，这些数量 疼痛和镇痛药的性别差异可能反映了 不同性别的疼痛调节系统有质的不同。 药理学和遗传学证据支持女性 小鼠具有性别特异性的非阿片类镇痛机制。 的 这种机制的神经化学鉴定仍然模糊，但 染色体区域（染色体8;大于52 cM）最近被 鉴定出含有一个基因，该基因介导内源性镇痛， 女性，但不是男性。 另一种性别特异性基因效应， 对急性、热伤害性感受和/或阿片类物质具有基础敏感性 男性而非女性的痛觉缺失定位于4号染色体 （40-80 cM）。初步数据表明，在这种情况下， 区域可以是Oprdl，其编码鼠d-阿片受体。 最后，已经鉴定出两种近交系小鼠， 男性显著高于女性（AKR），女性显著高于男性 (CBA)镇痛药对吗啡的敏感性 该项目的目标是 为了在这三个性别特异性基因中的每一个上取得进展， 效果：所采用的技术因情况而异。 数量性状基因座（QTL）定位技术将应用于 使用AKR和CBA菌株的吗啡镇痛， 确定雌性特异性QTL。 其他基因检测 群体，包括缺乏功能的转基因“敲除”小鼠， Oprdl基因的表达，将揭示 雄性特异的4号染色体QTL已经确定。 最后，初始 将采取步骤对雌性进行定位克隆- 特定的染色体8 QTL，以表征雌性特异性 镇痛机制 这项工作的临床应用可能包括 开发新的性别特异性镇痛策略。

Pain is a tremendous human health problem accounting for considerable morbidity and even contributing directly to mortality. Clinical pain conditions feature marked gender differences in their frequency and severity. One possible explanation for these differences is that the sexes may be differentially sensitive to pain. Indeed, when differences are found, females - of many species including rodents - appear to be more sensitive to and less tolerant of pain. The greater sensitivity to pain in females is accompanied by reduced sensitivity to analgesic drugs like morphine. Evidence exists suggesting that these quantitative sex differences in pain and analgesic may reflect the activation of qualitatively different pain modulatory systems in each sex. Pharmacological and genetic evidence support the contention that female mice possess a sex-specific, non-opioid analgesic mechanism. The neurochemical identification of this mechanism remains obscure, but a chromosomal region (chromosome 8; greater than 52 cM) has recently been identified that contains a gene which mediates endogenous analgesia in females, but not males. Another sex-specific gene effect, associated with basal sensitivity to acute, thermal nociception and/or opioid analgesia in males but not females, has been localized to chromosome 4 (40-80 cM). Preliminary data suggests that the relevant gene in this region may be Oprdl, which encodes the murine d-opioid receptor. Finally, two inbred mouse strains have been identified that show significant male greater than female (AKR) and female greater than male (CBA) analgesic sensitivity to morphine. The aims of this project are to make forward progress on each of these three sex-specific gene effects: the techniques to be employed are unique to each situation. Quantitative trait locus (QTL) mapping techniques will be applied to morphine analgesia using AKR and CBA strains in a directed attempt to identify female-specific QTLs. Testing of additional genetic populations, including transgenic "knock-out" mice lacking functional expression of the Oprdl gene, will reveal the generalizability of the male-specific chromosome 4 QTL already identified. Finally, initial steps will be taken towards the positional cloning of the female- specific chromosome 8 QTL, in order to characterize the female-specific analgesic mechanism. Clinical applications of this work may include the development of novel and sex-specific analgesic strategies.