Abstract/Details

Functional characterization of the <i>OPRM1</i> A118G single nucleotide polymorphism in mice


2011 2011

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Abstract (summary)

Endogenous opioids acting at μ-opioid receptors (MOPR) 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 MOPR 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. To clarify the functional mechanisms linking the OPRM1 A118G SNP to addiction and analgesia phenotypes, we derived a mouse model possessing the equivalent nucleotide/amino acid substitution in the mouse Oprm1 gene. I first evaluated MOPR expression and function using molecular and pharmacological techniques and, subsequently, investigated how these alterations affected basal and morphine-evoked responses using a variety of behavioral tasks. In order to better understand the synaptic and circuit-level alterations conferred by this SNP, we employed voltage-sensitive dye imaging in hippocampal slice preparations to evaluate basal and opioid-stimulated neuronal responses. Mice harboring this SNP (A112G) demonstrated several phenotypic similarities to humans carrying the A118G SNP, including reduced mRNA expression and morphine-mediated antinociception. We found additional phenotypes associated with this SNP including significant reductions of receptor protein levels, morphine-mediated hyperactivity, and locomotor sensitization, as well as sex-specific reductions in the rewarding properties of morphine and the aversive components of naloxone-precipitated morphine withdrawal. Functionally, this SNP reduced opioid-stimulated excitatory responses in the hippocampus. Together, these findings extend our understanding of the functional consequences of this SNP and support evidence suggesting that this SNP results in a loss of receptor function. Further cross-species analysis will allow us to investigate mechanisms and adaptations present in humans carrying this SNP.

Indexing (details)


Subject
Neurosciences
Classification
0317: Neurosciences
Identifier / keyword
Biological sciences; Mu-opioid receptors; Single nucleotide polymorphisms
Title
Functional characterization of the <i>OPRM1</i> A118G single nucleotide polymorphism in mice
Author
Mague, Stephen Daniel
Number of pages
140
Publication year
2011
Degree date
2011
School code
0175
Source
DAI-B 72/09, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781124731308
Advisor
Blendy, Julie
University/institution
University of Pennsylvania
University location
United States -- Pennsylvania
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3463021
ProQuest document ID
878679617
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/878679617
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