PATERNAL OPIOID EXPOSURE IMPARTS BIOBEHAVIORAL DEFICITS IN THEIR OFFSPRING

父亲接触阿片类药物会导致其后代出现生物行为缺陷

基本信息

批准号：
8461083
负责人：
THEODORE J CICERO
金额：
$ 32.83万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8461083
关键词：
Adolescence Adult Adult Children Adverse effects Affect Analgesics Behavior Binding Breeding Carcinogens Child Cognitive deficits Daughter Development Dextrorphan Dose Endocrine Epigenetic Process Exposure to Fathers Female Fertility Gender Generations Germ Lines Goals Gonadal Hormones Hormones Hour Individual Injection of therapeutic agent Knowledge Laws Levorphanol Life Style Litter Size Maternal Exposure Mediating Methadone Morphine Mutagens Nature Neonatal Mortality Occupations Opioid Opioid Receptor Outcome Partner in relationship Paternal Exposure Pharmaceutical Preparations Physiological Physiological Processes Pituitary Gland Pregnancy Outcome Process Property Rattus Recreational Drugs Reporting Research Risk Son Staging Stress Therapeutic Toxic Environmental Substances Woman biobehavior clinically significant drug of abuse male offspring pregnant preimplantation prescription opioid programs receptor response trend

项目摘要

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.

描述（由申请人提供）：父亲接触某些外源性物质，包括娱乐性和治疗性药物，可能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产生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。父亲吗啡暴露也会对妊娠结局和后代生存能力产生不利影响。在我们之前对大鼠的研究中，在与未用药的雌性交配前 24 小时注射一次吗啡就足以减少产仔数，显着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。我们还使用其他治疗范例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利影响。该项目的重点是我们之前在青春期长期接受吗啡治疗的雄性大鼠的成年后代中观察到的性别特异性内分泌缺陷。我们的首要目标是更清楚地定义成年男性和女性后代应激激素水平的影响本质。我们的第二个目标是确定父亲接触吗啡是否会影响后代的生育能力和/或后代男性和女性的生存能力和内分泌状态。我们的第三个目标是确定父亲接触吗啡是否会影响吗啡对成年后代的增强作用，这是其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阿片受体同质性、结合特性或受体后占据翻译过程的变化是否会因父系阿片类药物暴露而改变。关于母亲接触外源性物质对后代生存能力和功能的影响的研究催生了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的法律和教育计划。然而，尽管有证据表明可能具有临床意义，并且最近在识别潜在介导机制方面取得了进展，但对父亲接触外源性药物（特别是吗啡等治疗药物和滥用药物）后果的研究仅进行了零星的研究。因此，与母亲相比，与父亲接触吗啡等药物相关的风险人们知之甚少，甚至可能没有得到充分认识。鉴于最近处方阿片类药物的使用增加及其转用于非法使用的趋势，这一点尤其令人不安。当前的项目可能对许多风险基本上未被认识到的人具有临床意义，这些人的父亲接触阿片类药物，而他们自己可能没有直接接触吗啡或其他阿片类药物。