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Protein kinase C-mediated mu-opioid receptor phosphorylation and desensitization in rats, and its prevention during

Shaaban A Mousa1, Mohammed Shaqura, Jens Winkler

  • 1Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany Department of Anatomy, Ludwig Maximilian University Munich, Munich, Germany Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University, Jena, Germany Department of Internal Medicine, Paulinenkrankenhaus, Berlin, Germany.

Pain
|December 30, 2015
PubMed

Insights

Diabetic neuropathy impairs opioid pain relief by reducing mu-opioid receptor (MOR) function. This study reveals a RAGE-dependent PKC pathway causes MOR desensitization in sensory neurons, offering new therapeutic targets.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Endocrinology

Background:

  • Painful diabetic neuropathy is linked to reduced opioid effectiveness.
  • The exact mechanisms behind this impaired analgesia in sensory neurons are not fully understood.

Purpose of the Study:

  • To investigate the mechanisms of altered opioid responsiveness in early streptozotocin-induced diabetes in rats.
  • To identify key molecular players in sensory neurons contributing to impaired opioid analgesia.

Main Methods:

  • Utilized streptozotocin-induced diabetes model in rats.
  • Examined mu-opioid receptor (MOR) G protein coupling and phosphorylation.
  • Investigated the roles of Protein Kinase C (PKC), Receptor for Advanced Glycation End Products (RAGE), and advanced glycation end products (AGEs).
  • Employed PKC inhibitors, RAGE siRNA, and AGE formation inhibitors.

Main Results:

  • Diabetic rats showed reduced functional MOR G protein coupling and impaired peripheral opioid analgesia.
  • MORs in sensory neurons colocalized with activated PKC and RAGE.
  • MOR phosphorylation at Thr370, leading to desensitization, was mediated by RAGE-dependent PKC activation.
  • Interventions targeting PKC, RAGE, or AGE formation restored MOR function and analgesic efficacy.

Conclusions:

  • Demonstrated in vivo evidence of RAGE-dependent, PKC-mediated heterologous MOR phosphorylation and desensitization in sensory neurons during diabetic neuropathy.
  • Identified a novel mechanism contributing to impaired opioid responsiveness in diabetes.
  • Suggests potential therapeutic strategies for preventing or reversing opioid resistance in diabetic neuropathy.

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