Genetic behavioral screen identifies an orphan anti-opioid system

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Opioids are effective analgesics targeting the μ-opioid receptor (MOR).
• Opioid addiction remains a significant public health concern due to abuse potential.
• Genetic factors influencing opioid response require further elucidation.

Purpose of the Study:

• To develop a whole-animal screening platform for unbiased genetic discovery of opioid responsiveness modulators.
• To identify novel genes and pathways that regulate opioid signaling and behavior.
• To explore the therapeutic potential of identified targets for improving opioid safety.

Main Methods:

• Utilized forward genetics in *Caenorhabditis elegans* to screen for mutations affecting opioid response.
• Developed a whole-animal behavioral platform for high-throughput genetic screens.
• Investigated the function of identified genes, including GPR139, in mammalian models (mice).
• Examined GPR139 coexpression with MOR, its binding to MOR, and its effect on G protein signaling.

Main Results:

• Identified G protein-coupled receptor 139 (GPR139) as a conserved orphan receptor with anti-opioid activity.
• GPR139 is coexpressed with MOR in opioid-sensitive neural circuits.
• GPR139 binds to MOR and inhibits MOR-mediated G protein signaling.
• GPR139 deletion in mice modulated morphine-induced analgesia, reward, and withdrawal symptoms.
• Demonstrated enhanced opioid-induced neuronal inhibition in GPR139 knockout mice.

Conclusions:

• GPR139 acts as a negative regulator of MOR signaling, exhibiting anti-opioid properties.
• GPR139 represents a potential therapeutic target for enhancing opioid safety and mitigating addiction.
• The *C. elegans* platform offers a scalable approach for discovering G protein-coupled receptor signaling principles.