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

• 批准号: 8186085
• 负责人: THEODORE J CICERO
• 金额: $ 34.2万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/8186085
• 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

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.

描述（由申请方提供）：父方暴露于某些外源性物质，包括娱乐性和治疗性药物，可能对后代的生存力、发育和功能产生不利影响。吗啡是第一批被证明对后代有父源性影响的药物之一。它们包括生理、内分泌和认知缺陷以及对类阿片的药理反应改变。妊娠结局和后代的生存能力也受到父亲吗啡暴露的不利影响。 在我们以前的研究与大鼠，一个单一的吗啡注射前24小时交配的药物幼稚的女性是足以减少产仔数，显着增加新生儿死亡率和提高成年后代的敏感性吗啡的镇痛作用。我们还观察到不良影响的父亲吗啡暴露在植入前的过程中，窝仔数和激素水平的成年后代使用其他治疗模式。 该项目的重点是性别特异性的内分泌缺陷，我们以前观察到的成年后代的雄性大鼠长期治疗吗啡在青春期。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暴露于吗啡是否影响后代的生育能力和/或后代的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的强化特性，这是其滥用倾向的关键组成部分，在成年后代中。我们的最终目的是评估是否在“亩”或k阿片受体的同质性，结合特性或受体占领后的翻译过程的变化被改变了父亲阿片类药物暴露。 关于母体暴露于外源性物质对后代生存能力和功能的影响的研究导致了保护妇女的法律和教育方案，并帮助她们在怀孕期间做出更明智的生活方式决定。然而，尽管有可能具有临床意义的证据和最近在确定潜在介导机制方面取得的进展，但对父亲接触外源性药物，特别是治疗性和滥用药物（如吗啡）的后果的研究仅零星进行。因此，与母亲相比，与父亲接触吗啡等药物相关的风险知之甚少，可能也未得到重视。鉴于最近处方类阿片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的个人具有临床意义，这些人的风险在很大程度上没有被认识到，阿片类药物暴露的父亲的孩子可能没有直接接触吗啡或其他阿片类药物。 公共卫生关系：关于父亲暴露于外源性物质，特别是治疗性和滥用药物，如吗啡和相关阿片类药物的后果的研究，在过去的三十年里只是零星地进行，尽管有可能的临床意义的证据和最近的证据表明表观遗传男性生殖系遗传的潜力。鉴于最近处方类阿片的使用增加及其被转用于非法用途的趋势，我们的知识不足尤其令人不安。目前的项目，其重点是吗啡的家长介导的影响，可能有临床意义的大量个人的风险在很大程度上没有得到承认，儿子和女儿的阿片类药物暴露的父亲谁可能没有直接暴露于吗啡或另一种阿片类药物本身。