TRAFFICKING AND FUNCTION OF MU-OPIOD RECEPTOR GENETIC VARIANTS

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DESCRIPTION (provided by applicant): Opioid analgesics form the mainstay of pain management in our hospitals. However, their use is complicated by two main problems: variability in patient responses, and the development of tolerance and dependence leading to addiction. Addiction to opioids is a chronic and relapsing disorder for which there is currently no effective treatment. It is estimated that about 10% of the population in the United States is addicted to some illicit drug or other, making it a major socioeconomic problem. The main problem in addressing addiction is that we do not understand the molecular mechanisms underlying addiction. It is now established that genetic factors contribute to both these complicating aspects of opioids. The tolerance to pain, effective dosage of a defined opioid, efficacy of one drug vs. another, vulnerability to addiction, and effectiveness of addiction therapies, all depend on sequence variations that have been identified in different genes across populations. Understanding how these variations change opioid physiology in the brain will increase our understanding of pain and addiction, help in the development of new treatments for both these problems, and provide key steps in advancing personalized medicine. One key gene where genetic variations have been identified is OPRM1, which encodes the mu-opioid receptor (MOR), the target of many clinically abused drugs. Studies have linked prevalent single nucleotide polymorphisms in MOR to variations in pain tolerance, analgesia, vulnerability to opioid tolerance and dependence, alcoholism, and neuropsychiatric disorders. Importantly, whether and how these polymorphisms change MOR function at a molecular level is not known. We propose to use our expertise in developing high-resolution imaging assays to study GPCR trafficking in living cells to study how prevalent MOR polymorphisms change MOR function in neurons. The SNPs will be prioritized based on the known allelic frequency and linkage to clinical disorders, starting with A118G, the most prevalent and clinically relevant SNP. Specifically, we will test activation-induced signaling and trafficking of MOR - two fundamental events that define MOR function in neurons. Completion of this study will give us a better understanding of the normal variation of opioid signaling in physiologically relevant neurons, provide insights into functional selectivity of clinically relevant drugs, and help in developing o a platform to develop personalized doses and strategies for pain therapy and management of drug addiction.