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Antidepressants and the endogenous opioid system.

Lloyd D Fricker1, Aya Osman2, Achla Gupta3

  • 1Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA.

Biochemical Pharmacology
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Summary

The endogenous opioid system, involving mu-, delta-, and kappa-opioid receptors, is increasingly linked to major depressive disorder. Antidepressants like tianeptine and ketamine targeting these receptors offer rapid relief, suggesting a key role for the opioid system in depression.

Keywords:
EndorphinFluoxetineKetamineMajor depressive disorderOpioid receptorProenkephalinTianeptine

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Psychiatry

Background:

  • The endogenous opioid system comprises mu-, delta-, and kappa-opioid receptors (MOR, DOR, KOR) activated by various peptides.
  • This system is crucial for functions like analgesia, reward, and mood regulation.
  • Emerging evidence suggests a significant connection between the opioid system and major depressive disorder (MDD).

Purpose of the Study:

  • To review the evidence linking the opioid system to major depressive disorder.
  • To discuss the mechanisms of action for opioid-targeting drugs in depression treatment.
  • To identify limitations and future research directions in this field.

Main Methods:

  • Review of existing scientific literature on the endogenous opioid system and its relation to depression.
  • Analysis of studies on antidepressants that interact with opioid receptors, such as tianeptine, ketamine, and buprenorphine.
  • Examination of gene expression changes, like proenkephalin upregulation, following antidepressant treatment.

Main Results:

  • Antidepressants tianeptine (full MOR agonist) and ketamine (positive allosteric modulator) show rapid antidepressant effects by interacting with MOR.
  • Buprenorphine, a partial MOR agonist used for opioid use disorder, also demonstrates potential as a rapid-acting antidepressant.
  • Long-term treatment with selective serotonin reuptake inhibitors (SSRIs) like fluoxetine leads to increased proenkephalin gene expression in mice.

Conclusions:

  • The findings suggest a substantial role for the endogenous opioid system in major depressive disorder.
  • Opioid receptor modulation represents a promising therapeutic avenue for rapid-acting antidepressant treatments.
  • Further research is needed to fully elucidate the strengths, limitations, and therapeutic potential of targeting the opioid system for depression.