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Clinical opioids differentially induce co-internalization of μ- and δ-opioid receptors

Fenghua Bao1,2, Chang-Lin Li1,2,3, Xu-Qiao Chen4

  • 11 Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.

Molecular Pain
|March 29, 2018
PubMed

Insights

Clinical μ-opioid receptor (MOR) targeting opioids like morphine, fentanyl, and methadone, but not tramadol, cause MOR to co-internalize with δ-opioid receptors (DOR). This interaction may contribute to opioid-induced analgesic tolerance.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Opioid receptors are crucial for spinal analgesia, with the μ-opioid receptor (MOR) being a primary target for clinical analgesics.
  • Mechanisms underlying MOR-mediated analgesia and tolerance are not fully understood.
  • MOR can form heteromers with δ-opioid receptors (DOR), influencing receptor processing.

Purpose of the Study:

  • To investigate the role of MOR/DOR heteromerization in the cellular response to clinical opioids.
  • To determine if MOR and DOR co-internalization is a common mechanism for MOR-targeting analgesics.
  • To explore the link between MOR/DOR co-internalization and the development of opioid-induced tolerance.

Main Methods:

  • Utilized transfected human embryonic kidney 293 cells and primary sensory neurons.
  • Examined the effects of clinical opioids (morphine, fentanyl, methadone, tramadol) on MOR and DOR localization.
  • Assessed receptor co-internalization and co-degradation following opioid treatment.
  • Evaluated the induction of analgesic tolerance in response to drug exposure.

Main Results:

  • Morphine, fentanyl, and methadone, unlike tramadol, induced co-internalization of MOR with DOR in both cell lines and neurons.
  • Prolonged morphine treatment resulted in the co-degradation of MOR and DOR.
  • Fentanyl and methadone, similar to morphine, induced significant analgesic tolerance, whereas tramadol did not.

Conclusions:

  • Clinical MOR-targeting opioids (morphine, fentanyl, methadone) promote MOR and DOR co-internalization.
  • This co-internalization process, potentially leading to co-degradation, may underlie the development of analgesic tolerance to these common opioids.
Keywords:
clinical opioidsmorphinereceptor internalizationµ-opioid receptor

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