15 years of genetic approaches in vivo for addiction research: Opioid receptor and peptide gene knockout in mouse models of drug abuse.
15 years of genetic approaches in vivo for addiction research: Opioid receptor and peptide gene knockout in mouse models of drug abuse.
复制标题
DOI：
10.1016/j.neuropharm.2013.08.028
复制
发表时间：
2014-01
影响因子：
4.7
通讯作者：
Befort K
中科院分区：
文献类型：
--
作者：
Charbogne P;Kieffer BL;Befort K
内源性阿片系统在整个大脑强化回路中都有表达，并在奖赏处理、情绪控制和成瘾发展中发挥重要作用。该神经调节系统由Mu、Delta和Kappa三种受体组成，与前脑啡肽前体(β-Endphin)、前脑啡肽原(PENK)和前强啡肽前体(PDyn)等阿片肽相互作用。针对阿片系统每个基因的基因敲除小鼠是近20年前创造的。延伸经典药理学，这些突变小鼠代表着独特的工具，可以梳理出每个阿片受体和肽在体内的特定作用，也是了解阿片系统如何调节滥用药物的行为影响的有效方法。本审查总结了这些研究，重点是主要的滥用药物，包括吗啡/海洛因、大麻素、精神刺激剂、尼古丁或酒精。总的来说，遗传数据将u受体设置为吗啡和海洛因的主要靶点。此外，该受体对于调节滥用的非阿片类药物的奖赏特性是必不可少的，β-内啡肽对可卡因和尼古丁具有明显的暗示作用。Delta受体活性可降低焦虑和抑郁样行为的水平，并促进吗啡与环境的联系。Penk参与了这些过程，Delta/Penk信号可能调节酒精摄入量。Kappa受体主要与pDyn多肽相互作用以限制药物奖赏，并介导大麻和尼古丁的烦躁效应。在应激条件下，Kappa/强啡肽活性也增加了对可卡因奖励的敏感性。阿片系统仍然是开发成瘾个体成功疗法的最佳候选者，通过新兴的遗传和成像技术在系统水平上了解阿片类药物介导的过程是下一个具有挑战性的目标，也是成瘾研究的一个有前途的途径。
The endogenous opioid system is expressed throughout the brain reinforcement circuitry, and plays a major role in reward processing, mood control and the development of addiction. This neuromodulator system is composed of three receptors, mu, delta and kappa, interacting with a family of opioid peptides derived from POMC (β-endorphin), preproenkephalin (pEnk) and preprodynorphin (pDyn) precursors. Knockout mice targeting each gene of the opioid system have been created almost two decades ago. Extending classical pharmacology, these mutant mice represent unique tools to tease apart the specific role of each opioid receptor and peptide in vivo, and a powerful approach to understand how the opioid system modulates behavioral effects of drugs of abuse. The present review summarizes these studies, with a focus on major drugs of abuse including morphine/heroin, cannabinoids, psychostimulants, nicotine or alcohol. Genetic data, altogether, set the mu receptor as the primary target for morphine and heroin. In addition, this receptor is essential to mediate rewarding properties of non-opioid drugs of abuse, with a demonstrated implication of β-endorphin for cocaine and nicotine. Delta receptor activity reduces levels of anxiety and depressive-like behaviors, and facilitates morphine-context association. PEnk is involved in these processes and delta/pEnk signaling likely regulates alcohol intake. The kappa receptor mainly interacts with pDyn peptides to limit drug reward, and mediate dysphoric effects of cannabinoids and nicotine. Kappa/dynorphin activity also increases sensitivity to cocaine reward under stressful conditions. The opioid system remains a prime candidate to develop successful therapies in addicted individuals, and understanding opioid-mediated processes at systems level, through emerging genetic and imaging technologies, represents the next challenging goal and a promising avenue in addiction research.
登录
查看更多内容
影响因子：
2.9
作者：
Bruchas MR;Land BB;Chavkin C
通讯作者：
Chavkin C
影响因子：
13.5
作者：
Chung, Paul Chu Sin;Kieffer, Brigitte L.
通讯作者：
Kieffer, Brigitte L.
影响因子：
3.4
作者：
Chefer, VI;Shippenberg, TS
通讯作者：
Shippenberg, TS
影响因子：
3.3
作者：
Chefer, VI;Kieffer, BL;Shippenberg, TS
通讯作者：
Shippenberg, TS
影响因子：
64.8
作者：
COMB, M;SEEBURG, PH;HERBERT, E
通讯作者：
HERBERT, E