Investigating the role of GPR139 in opioid withdrawal
Active Project Grant Awarded Last action
- Award ID
- F32DA065328
- Recipient
-
University Of Florida UEI NNFQH1JAPEP3
- Awarding agency
-
National Institute on Drug Abuse
National Institutes of Health, Department of Health and Human Services
- Obligated
- $76,300
Award facts
- Assistance listing
- 93.279 Drug Use and Addiction Research Programs
- Completion date 0% complete
- Place of performance
- Miami, FL 33136, USA
Award details come from USAspending.gov.
Description
- Abstract
- Withdrawal symptoms are a major factor contributing to relapse in opioid use disorder. Opioid analgesics bind to the Μ-opioid receptor (MOR) to produce analgesia, euphoria, and-when a dose is too high-respiratory depression. However, chronic MOR activation induces opioid tolerance and dependence. When opioid use is discontinued, physical and emotional withdrawal symptoms set in. Current withdrawal treatments are inadequate to fully control the relapse. We have identified a new target to potentially ameliorate the withdrawal issues, an orphan G protein-coupled receptor GPR139. GPR139 is CO-expressed with MOR in key brain regions associated with withdrawal, including the locus coeruleus (LC) and the medial habenula (MHB). Our preliminary data shows that GPR139 counteracts the effects of MOR including its regulation of camp production. Importantly, mice with global ablation of GPR139 show decreased withdrawal symptoms. The hypothesis of this proposal is that GPR139 expression in the LC and MHB contribute to physical and emotional withdrawal, respectively, by modulating camp levels. This hypothesis will be tested by two complimentary aims. Aim 1) to test the importance of the LC and MHB in opioid withdrawal, genetic and pharmacological approaches will probe the necessity of GPR139 expression and activity in these regions. First, mice with LC-specific or MHB-specific ablation of GPR139 will be tested for physical and emotional withdrawal. In a separate experiment, mice will be infused with a GPR139-specific antagonist in the LC or MHB prior to tests of physical and emotional withdrawal. Aim 2) to test the intracellular mechanisms of GPR139 during withdrawal, camp dynamics in EX vivo brain slices will be visualized in real-time using mice that express a camp-encoded reporter (CAMPER) in MOR neurons. Levels of camp will be monitored during withdrawal states while activating or blocking GPR139 activity and its transduction mechanisms. We will further test the role of camp in withdrawal behavior using a neuronal-specific chemogenetic approach. The proposed research will improve our understanding of genetic factors that shape the withdrawal behaviors in different brain regions while providing a validation of a novel pharmacological target for intervention.
Quick answers
Who received award F32DA065328?
F32DA065328 was awarded to University Of Florida by National Institute on Drug Abuse (National Institutes of Health) on November 30, 2026.
How much is award F32DA065328 worth?
$76,300 has been obligated on F32DA065328.
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