FUNCTIONAL CHARACTERIZATION OF THE OPRM1 A118G

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 thi