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Genetic behavioral screen identifies an orphan anti-opioid system

Dandan Wang1, Hannah M Stoveken1, Stefano Zucca1

  • 1Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.

Science (New York, N.Y.)
|August 17, 2019
PubMed

Insights

Researchers discovered G protein-coupled receptor 139 (GPR139), an anti-opioid target. Deleting GPR139 in mice altered morphine effects, suggesting GPR139 can enhance opioid safety and reduce abuse potential.

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.

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