Abstract

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, NH(2)-CH-Ph-P(O)(OH)CH(2)-CH-CH(2)Ph(p-Ph)-CONH-CH-CH(3)-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 μ-, δ-, and κ-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 μM)/thiorphan (1-100 μM) combinations or by P8B (1-100 μM) 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.

Links

Publisher Full Text

Authors

Schreiter A, Gore C, Labuz D, Fournie-Zaluski MC, Roques BP, Stein C, Machelska H

Institution

Klinik für Anästhesiologie und operative Intensivmedizin, Freie Universität Berlin, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.

Source

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26:12 2012 Dec pg 5161-71

MeSH

Alanine
Amino Acid Sequence
Animals
Antibodies
Antigens, CD13
Dose-Response Relationship, Drug
Dynorphins
Enkephalin, Leucine
Enkephalin, Methionine
Enzyme Inhibitors
Flow Cytometry
Hindlimb
Inflammation
Leucine
Leukocytes
Male
Neprilysin
Neurons
Opioid Peptides
Pain
Pain Threshold
Phosphinic Acids
Rats
Rats, Wistar
Receptors, Opioid
Thiorphan

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22923332