ORPHANIN SYSTEM--ROLE IN STRESS AND ADDICTION

孤啡肽/孤啡肽系统（OFQ system）是一种新的肽能系统，在进化上与内源性阿片类物质相关，但具有独特的生物化学、解剖学和功能特性。 工作假设是，OFQ系统在调节压力反应的生物学、奖励机制的生物学以及压力和奖励机制之间的相互作用中发挥作用，因为它们影响药物相关行为。 这一假设是基于迄今为止收集的几条解剖学和功能证据。 然而，在探讨这些职能问题之前，对这一制度的一些基本特征仍有许多需要了解的地方。 因此，本申请提出确定应激（新奇和约束）是否调节OFQ或其相关受体ORL 1，特别是脑区域，并确定OFQ在这些应激敏感区域中调节边缘-下丘脑-垂体-肾上腺（LHPA）轴的能力（目的I）。 它探讨了解剖学特征的OFQ系统的上下文中的mesocorticolimbic多巴胺能系统，它似乎是高度表达，并解决了是否OFQ和ORL 1的多巴胺能神经元内存在的问题，以及它们是否位于电路，可以调节多巴胺能传输（目的II）。 最后，在上述电路的背景下，它检查了这个系统是如何调制的慢性管理的阿片类药物和精神兴奋剂的条件下，导致敏感这些药物。反过来，它询问OFQ是否能够改变压力和非压力条件下的药物致敏过程（目的III）。 分子、解剖和行为工具的组合将被用来解决这些问题。总之，这些研究不仅将揭示这种新的肽能系统的功能，但也将提供新的见解之间的重要接口的压力机制，多巴胺能机制和药物滥用。

This proposal is focused on studying the newly discovered Orphanin/Nociceptin system (OFQ system), a new peptidergic system, evolutionarily related to the endogenous opioids but exhibiting distinct biochemical, anatomical and functional properties. The working hypothesis is that the OFQ systems plays a role in the regulation of the biology of stress responsiveness, the biology of reward mechanisms, and the interactions between stress and reward mechanisms as they impact on drug-related behavior. This hypothesis is based on several lines of anatomical and functional evidence gathered to date. However, much remains to be learned about some of the fundamental features of this system before pursuing these functional questions. Thus, this application proposes to determine whether stress (novelty and restraint) regulates OFQ or its associated receptor, ORL1, in particular brain regions, and to ascertain the ability of OFQ in these stress-sensitive regions to modulate the limbic- hypothalamo-pituitary-adrenal (LHPA) axis) (Aim I). It explores the anatomical features of the OFQ system in the context of the mesocorticolimbic dopaminergic system, where it appears to be highly expressed, and addresses the issue of whether or not OFQ and ORL1 are present within dopaminergic neurons, and whether they are located in circuits which could modulate dopaminergic transmission (Aim II). Finally, in the context of the above circuits, it examines the way this system is modulated by chronic administration of opiates and psychostimulants under conditions which lead to sensitization to these drugs. In turn, it asks whether OFQ is able to alter the course of drug sensitization in stressful and non-stressful conditions (Aim III). A combination of molecular, anatomical, and behavioral tools will be used to address these questions. Together, these studies will not only shed light on the functioning of this novel peptidergic system, but will also provide new insights on the important interface between stress mechanisms, dopaminergic mechanisms, and substance abuse.