Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, TRL, PA 19104, USA.
Drug Alcohol Depend. 2010 May 1;108(3):172-82. doi: 10.1016/j.drugalcdep.2009.12.016. Epub 2010 Jan 13.
Endogenous opioids acting at mu-opioid receptors mediate many biological functions. Pharmacological intervention at these receptors has greatly aided in the treatment of acute and chronic pain, in addition to other uses. However, the development of tolerance and dependence has made it difficult to adequately prescribe these therapeutics. A common single nucleotide polymorphism (SNP), A118G, in the mu-opioid receptor gene can affect opioid function and, consequently, has been suggested to contribute to individual variability in pain management and drug addiction. Investigation into the role of A118G in human disease and treatment response has generated a large number of association studies across various disease states as well as physiological responses. However, characterizing the functional consequences of this SNP and establishing if it causes or contributes to disease phenotypes have been significant challenges. In this manuscript, we will review a number of association studies as well as investigations of the functional impact of this gene variant. In addition, we will describe a novel mouse model that was generated to recapitulate this SNP in mice. Evaluation of models that incorporate known human genetic variants into a tractable system, like the mouse, will facilitate the understanding of discrete contributions of SNPs to human disease.
内源性阿片肽通过作用于μ-阿片受体来调节许多生物学功能。这些受体的药理学干预极大地帮助了急慢性疼痛的治疗，除此之外还有其他用途。然而，由于产生了耐受性和依赖性，这些治疗方法的应用受到了限制。μ-阿片受体基因中的常见单核苷酸多态性（SNP）A118G 可以影响阿片类药物的功能，因此，有人认为它导致了个体对疼痛管理和药物成瘾的差异。对 A118G 在人类疾病和治疗反应中的作用的研究已经在各种疾病状态和生理反应中产生了大量的关联研究。然而，确定这种 SNP 的功能后果并确定它是否导致或促成疾病表型一直是一个巨大的挑战。在本文中，我们将回顾一些关联研究以及对该基因变异的功能影响的研究。此外，我们将描述一种新的小鼠模型，该模型在小鼠中模拟了这种 SNP。评估将已知的人类遗传变异纳入可处理系统（如小鼠）的模型将有助于理解 SNP 对人类疾病的离散贡献。
