Pain inhibition by blocking leukocytic and neuronal opioid peptidases in peripheral inflamed tissue

Inflammatory pain can be controlled by entodogenous 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 entodopeptidase (NEP; thiorphan),and a dual inhibitor, NH2 -CH-Ph-P(O)(OH)CH2 -CHCH2 Ph(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  -,  -, and  -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.

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