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μ-Opioid receptor desensitization: homologous or heterologous?

Javier Llorente1, Janet D Lowe, Helen S Sanderson

  • 1School of Physiology & Pharmacology, University of Bristol, Bristol, UK.

The European Journal of Neuroscience
|September 26, 2012
PubMed

Insights

Micro-opioid receptor (MOPr) desensitization shifts from heterologous in immature neurons to homologous in mature neurons. This age-dependent change in MOPr desensitization mechanisms is linked to developmental alterations in G-protein-coupled receptor kinases (GRKs).

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Micro-opioid receptor (MOPr) desensitization mechanisms are debated, with proposed roles for receptor phosphorylation, G-protein-coupled receptor kinases (GRKs), and effector pathway modulation.
  • Existing research presents conflicting findings regarding homologous versus heterologous desensitization and the underlying molecular pathways.

Purpose of the Study:

  • To investigate the developmental changes in MOPr desensitization mechanisms in rat locus coeruleus (LC) neurons.
  • To determine whether MOPr desensitization is homologous or heterologous and identify the contributing molecular factors in immature versus mature neurons.

Main Methods:

  • Electrophysiological recordings in brainstem locus coeruleus (LC) neurons from rats of different ages (immature vs. mature).
  • Assessment of MOPr desensitization in response to opioid peptides (methionine enkephalin, DAMGO).
  • Evaluation of desensitization in relation to other receptors (α(2)-adrenoceptors, SST(2) receptors) and measurement of GRK2 expression levels.

Main Results:

  • In mature rat LC neurons, MOPr desensitization was homologous and not heterologous to α(2)-adrenoceptors and SST(2) receptors.
  • In immature neurons, MOPr desensitization was heterologous and occurred downstream of the receptor, independent of protein kinase C or c-Jun N-terminal kinase.
  • A decrease in GRK2 expression correlated with the shift from heterologous to homologous desensitization with age.

Conclusions:

  • MOPr desensitization mechanisms undergo significant developmental changes in the brainstem LC.
  • In mature neurons, MOPr desensitization is primarily homologous, suggesting pathways independent of G protein βγ subunit sequestration or ion channel modulation.
  • Findings highlight the importance of considering neuronal development when interpreting MOPr desensitization studies.

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