PATERNAL OPIOID EXPOSURE IMPARTS BIOBEHAVIORAL DEFICITS IN THEIR OFFSPRING

描述（由申请人提供）：父亲接触某些外源性药物，包括娱乐性和治疗性药物，会对后代的生存能力、发育和功能产生不利影响。吗啡是最早被证明对后代具有父系影响的药物之一。它们包括生理、内分泌和认知缺陷以及对阿片类药物的药理反应改变。妊娠结局和后代生存能力也受到父亲吗啡暴露的不利影响。在我们之前对大鼠的研究中，在与未用药的雌性交配前24小时单次注射吗啡足以减少产仔数，显著增加新生儿死亡率，并增强成年后代对吗啡镇痛作用的敏感性。我们还观察了父亲吗啡暴露对植入前过程、产仔数和成年后代激素水平的不良影响。我们之前在青春期长期服用吗啡的雄性大鼠成年后代中观察到的性别特异性内分泌缺陷。我们的第一个目标是更清楚地定义对成年雄性和雌性后代的应激激素水平的影响的性质。我们的第二个目的是确定父亲接触吗啡是否会影响后代的生育能力和/或后代雄性和雌性的生存能力和内分泌状况。我们的第三个目标是确定父亲接触吗啡是否会影响成年后代对吗啡的强化特性，这是吗啡滥用倾向的一个关键组成部分。我们的最终目的是评估“mu”或k类阿片受体同质性、结合特性或受体占领后翻译过程的变化是否会因父亲接触阿片而改变。对母亲暴露于外源性物质对后代生存能力和功能的影响的研究已经产生了法律和教育计划，以保护妇女，并帮助她们在怀孕期间做出更明智的生活方式决定。然而，关于父亲暴露于外源性药物的后果的研究，特别是治疗和滥用药物，如吗啡，尽管有证据表明可能具有临床意义，并且最近在确定潜在的介导机制方面取得了进展，但只进行了零星的研究。因此，与母亲相比，父亲接触吗啡等药物的风险知之甚少，甚至可能没有得到充分的认识。鉴于最近处方阿片类药物的使用增加并转为非法使用的趋势，这一点尤其令人不安。目前的项目可能对大量风险在很大程度上未被识别的个体具有临床意义，阿片类药物暴露父亲的孩子可能没有直接接触吗啡或其他阿片类药物。

DESCRIPTION (provided by applicant): Paternal exposure to certain exogenous agents, including recreational and therapeutic drugs, can adversely affect offspring viability, development and function. Morphine was one of the first drugs shown to have paternal-mediated consequences for offspring. They include physiological, endocrine and cognitive deficits and an altered pharmacological response to opioids. Pregnancy outcome and offspring viability are also adversely affected by paternal morphine exposure. In our previous studies with rats, a single morphine injection 24 hours before mating with a drug naive female was sufficient to reduce litter size, markedly increase neonatal mortality and enhance adult offspring sensitivity to analgesic effects of morphine. We also observed adverse effects of paternal morphine exposure on pre-implantation processes, litter sizes, and hormone levels in adult offspring using other treatment paradigms. The proposed project focuses on gender-specific endocrine deficits we previously observed in adult offspring of male rats chronically treated with morphine during adolescence. Our first aim is to more clearly define the nature of the effects on stress hormone levels in adult male and female offspring. Our second aim is to determine whether paternal exposure to morphine affects offspring fertility and/or the viability and endocrine status of males and females of subsequent generations. Our third aim will be to determine whether paternal exposure to morphine affects the reinforcing properties of morphine, a key component of its abuse liability, in adult offspring. Our final aim is to assess whether changes in "mu" or k opioid receptor homogeneity, binding properties or post receptor occupation translational processes are altered by paternal opioid exposure. Research on the effects of maternal exposure to exogenous agents on offspring viability and function has resulted in laws and educational programs to protect women and help them make more informed lifestyle decisions while pregnant. Research on the consequences of paternal exposure to exogenous agents however, particularly therapeutic and abused drugs like morphine, has been carried out only sporadically despite evidence of possible clinical significance and recent advancements in the identification of potential mediating mechanisms. As a result, the risks associated with paternal, compared to maternal, exposure to drugs like morphine are poorly understood and perhaps under appreciated. This is particularly troubling in view of the recent trend toward the increased use of prescription opioids and their diversion for illegal use. The current project could have clinical significance for a substantial number of individuals who's risk has largely gone unrecognized, children of opioid exposed fathers who may not have direct exposure to morphine or another opioid themselves. PUBLIC HEALTH RELEVANCE: Research on the consequences of paternal exposure to exogenous agents, particularly therapeutic and abused drugs like morphine and related opioids, has been carried out only sporadically over the past three decades despite evidence of possible clinical significance and recent evidence indicating the potential for epigenetic male germ line inheritance. This shortfall in our knowledge is particularly troubling in view of the recent trend toward the increased use of prescription opioids and their diversion for illegal use. The current project, which focuses on the effects of paternal-mediated effects of morphine, could have clinical significance for a substantial number of individuals who's risk has largely gone unrecognized, sons and daughters of opioid exposed fathers who may not have direct exposure to morphine or another opioid themselves.