Longterm Behavioral Effects of Neonatal Pain and Morphine Treatment in Mice

描述（由申请人提供）：新生儿ICU中的危重早产儿受到严重压力，并经历许多痛苦的过程，因此他们经常使用吗啡等麻醉剂进行治疗，以尝试缓解他们的压力和疼痛反应-有时长达数周或数月。这是一个重要的卫生保健问题，原因有两个：1）新生儿压力/疼痛被认为对发育中的大脑有长期的不良影响，包括行为障碍，如抑郁症和成瘾; 2）也有人担心长期暴露于麻醉剂，试图改善新生儿压力/疼痛反应的神经发育影响。本探索性资助申请是为响应RFA-DA-06-005“疼痛治疗中的处方阿片类药物使用和滥用”而编写的。“对于这些研究，我们开发了一种独特的早产新生儿疼痛/压力和麻醉剂暴露的小鼠模型，模拟了新生儿ICU中危重早产儿的临床状况。我们还在我们的发育神经药理学小组和Chavkin实验室之间建立了一个新的合作关系，该合作关系的重点是了解疼痛/压力对成人成瘾/奖励行为的影响机制。我们申请的总体目标是使用我们独特的小鼠模型来提高我们对新生儿应激和慢性麻醉剂暴露对成人成瘾行为的长期影响的理解，并探索这些长期影响的机制。我们的中心假设是，反复的新生儿疼痛/压力诱导内源性强啡肽的释放，持续激活κ阿片受体，导致随后的敏感性，在以后的生活中经历的麻醉剂的奖励性质。此外，我们假设，新生儿吗啡治疗改善这些长期影响新生儿疼痛/压力成人成瘾和抑郁行为，通过减少新生儿释放内源性强啡肽。我们将致力于以下具体目标：1。检查长期的，性别特异性的影响，新生儿疼痛/压力，有或没有吗啡治疗，成人成瘾和抑郁行为; 2。使用前强啡肽和κ阿片受体基因敲除小鼠，我们将测试我们的中心假设，新生儿疼痛/压力的长期影响的潜在机制及其对成人成瘾和抑郁行为的治疗。了解新生儿压力和麻醉剂对成人成瘾和抑郁行为的长期影响，将有助于管理这些脆弱婴儿的临床医生更安全有效地照顾他们。

DESCRIPTION (provided by applicant): Critically ill premature infants in neonatal ICUs are severely stressed and undergo numerous painful procedures, so they are often treated with narcotics such as morphine to try and relieve their stress and pain responses-sometimes for weeks or months. This is an important health care issue for two reasons: 1) neonatal stress/pain is believed to have long-term adverse effects on the developing brain, including behavioral disorders such as depression and addiction; and 2) there are also concerns about the neurodevelopmental effects of prolonged narcotic exposure used to try and ameliorate neonatal stress/pain responses. This exploratory grant application is written in response to RFA-DA-06-005 "Prescription Opioid Use and Abuse in the Treatment of Pain." For these studies, we have developed a unique mouse model of preterm neonatal pain/stress and narcotic exposure which mimics the clinical condition of critically ill preterm infants in the neonatal ICU. We have also developed a new collaboration between our developmental neuropharmacology group and the Chavkin lab-which is focused on understanding mechanisms for the effects of pain/stress on adult addiction/reward behavior. The overall objective of our application is to use our unique mouse model to improve our understanding of the long-term effects of neonatal stress and chronic narcotic exposure on adult addictive behavior, and to explore mechanisms for these long-term effects. Our central hypothesis is that repeated neonatal pain/stress induces release of endogenous dynorphin peptides which persistently activates kappa opioid receptors which causes a subsequent sensitization to the rewarding properties of narcotics experienced later in life. Further, we hypothesize that neonatal morphine treatment ameliorates these long-term effects of neonatal pain/stress on adult addictive and depressive behavior by decreasing the neonatal release of endogenous dynorphin. We will address the following Specific Aims: 1. To examine long-term, gender-specific effects of neonatal pain/stress, with or without morphine treatment, on adult addictive and depressive behavior; 2. Using prodynorphin and kappa opioid receptor knockout mice, we will test our central hypothesis regarding potential mechanisms for the long-term effects of neonatal pain/stress and its treatment on adult addictive and depressive behaviors. Understanding the long-term effects of neonatal stress and narcotics on adult addictive and depressive behaviors will help clinicians who manage these vulnerable infants to care for them more safely and effectively.