Journal
FASEB JOURNAL
Volume 26, Issue 12, Pages 5161-5171Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.12-208678
Keywords
immune cells; sensory nerves; analgesia
Categories
Funding
- Deutsche Forschungsgemeinschaft [MA 2437/2-1, STE 477/9-1]
Ask authors/readers for more resources
Inflammatory pain can be controlled by endogenous opioid peptides. Here we blocked the degradation of opioids in peripheral injured tissue to locally augment this physiological system. In rats with hindpaw inflammation, inhibitors of aminopeptidase N (APN; bestatin) or neutral endopeptidase (NEP; thiorphan), and a dual inhibitor, NH2-CH-Ph-P(O)(OH)CH2-CH-CH2Ph(p-Ph)-CONH-CH-CH3-COOH (P8B), were applied to injured paws. Combined bestatin (1.25-5 mg)/thiorphan (0.2-0.8 mg) or P8B (0.0625-1 mg) alone elevated mechanical nociceptive thresholds to 307 and 227% of vehicle-treated controls, respectively. This analgesia was abolished by antibodies to methionine-enkephalin, leucine-enkephalin, and dynorphin A 1-17, by peripherally restricted and by selective mu-, delta-, and kappa-opioid receptor antagonists. Flow cytometry and photospectrometry revealed expression and metabolic activity of APN and NEP on macrophages, granulocytes, and sciatic nerves from inflamed tissue. Radioimmunoassays showed that inhibition of leukocytic APN and NEP by bestatin (5-500 mu M)/thiorphan (1-100 mu M) combinations or by P8B (1-100 mu M) prevented the degradation of enkephalins. Blockade of neuronal peptidases by bestatin (0.5-10 mM)/thiorphan (0.1-5 mM) or by P8B (0.1-10 mM) additionally hindered dynorphin A 1-17 catabolism. Thus, leukocytes and peripheral nerves are important sources of APN and NEP in inflamed tissue, and their blockade promotes peripheral opioid analgesia.-Schreiter, A., Gore, C., Labuz, D., Fournie-Zaluski, M.-C., Roques, B. P., Stein, C., Machelska, H. Pain inhibition by blocking leukocytic and neuronal opioid peptidases in peripheral inflamed tissue. FASEB J. 26, 5161-5171 (2012). www.fasebj.org
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available