Opioid analgesia in inflammation: activation by catecholamines and inhibitors of opioid peptide-degrading enzymes

• Applicants: Professorin Dr. Halina Machelska-Stein; Professor Dr. Christoph Stein
• Subject Area: Anaesthesiology
• Term: from 2008 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 55231961

• Final Report Year: 2014

Final Report Abstract

Our findings indicate that in painful inflamed tissue APN and NEP are metabolically active on immune cells and peripheral nerves. Granulocytes and macrophages are predominant leukocyte populations that express active APN and NEP preferentially degrading ENKs. The enzymatic activity of NEP, but not of APN, expressed on peripheral nerves is enhanced in inflamed tissue. Besides Met-ENK and Leu-ENK, DYN emerges as an additional substrate of neuronal APN and NEP. Blocking leukocytic and neuronal APN and NEP prevents the catabolism of ENKs and DYN which activate peripheral µ-, δ-, and κ-opioid receptors to locally inhibit inflammatory pain.

Publications

• Modulation of peripheral sensory neurons by the immune system: implications for pain therapy. Pharmacol Rev 2011, 63: 860-881
  Stein C, Machelska H
  
• Pain inhibition by blocking leukocytic and neuronal opioid peptidases in peripheral inflamed tissue. FASEB J 2012, 26:5161-5171
  
  (See online at https://doi.org/10.1096/fj.12-208678)
• Endogene Opioide: Ihre Wirkung kann man deutlich verstärken. In: AINS (Anästhesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie) 2013, 3:142-143
  Machelska H, Stein C
  
• Targeting inflammation and wound healing by opioids. Trends Pharmacol Sci 2013, 34:303-312
  Stein C, Küchler S
  (See online at https://doi.org/10.1016/j.tips.2013.03.006)
• Peripheral neuroimmune interactions and neuropathic pain. In: Neuroinflammation and Neurodegeneration. Eds. Peterson PK, Torborek M., Springer, New York, NY, 2014, pp 105-116. 978-1-4939-1070-0
  Machelska H
  (See online at https://doi.org/10.1007/978-1-4939-1071-7_6)