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Desensitization of functional µ-opioid receptors increases agonist off-rate

John T Williams1

  • 1Vollum Institute, Oregon Health and Science University, Portland, Oregon williamj@ohsu.edu.

Molecular Pharmacology
|April 22, 2014
PubMed

Insights

Opioid receptor desensitization reduces the number of functional receptors, leading to decreased signaling. This desensitization impacts agonist affinity and receptor number, affecting downstream cellular responses.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Opioid receptor desensitization is a key mechanism influencing opioid efficacy and tolerance.
  • Desensitization of µ-opioid receptors (MORs) occurs rapidly after agonist exposure and is homologous.
  • The precise molecular mechanisms underlying MOR desensitization, whether reduced receptor number or impaired coupling, remain under investigation.

Purpose of the Study:

  • To investigate the kinetic changes in MOR-mediated G protein-coupled inwardly rectifying potassium (GIRK) channel activity before and after desensitization.
  • To differentiate between a reduction in receptor number and a decrease in receptor-G protein coupling as mechanisms of MOR desensitization.
  • To examine the impact of desensitization on agonist affinity and receptor number using photolabile ligands.

Main Methods:

  • Utilized photolysis of caged ligands, including caged naloxone (antagonist) and a caged enkephalin agonist, to probe MOR function.
  • Measured MOR-induced GIRK currents by applying caged ligands and observing changes in conductance kinetics.
  • Assessed the effects of acute desensitization and irreversible blockade with β-chlornaltrexamine (β-CNA) on current kinetics.

Main Results:

  • Desensitization significantly decreased the rate of antagonist-induced current block, suggesting a reduced number of available receptors.
  • Irreversible antagonist blockade with β-CNA did not mimic the desensitization-induced changes in current decay kinetics.
  • Desensitization and irreversible blockade increased the latency to peak GIRK current, indicating impaired agonist-induced signaling and potentially reduced agonist affinity.

Conclusions:

  • Opioid receptor desensitization primarily reduces the number of functional MORs rather than solely impairing receptor-G protein coupling.
  • The remaining active MORs exhibit reduced affinity for agonists following desensitization.
  • These findings clarify the molecular basis of opioid receptor desensitization, impacting our understanding of opioid tolerance and withdrawal.

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