Paradoxical analgesia induced by low doses of naloxone is not potentiated by complete inhibition of enkephalin degradation.
The involvement of a presynaptic autoinhibition of endogenous enkephalin release has been suggested as a possible explanation for the paradoxical analgesia induced by low doses of naloxone. This hypothesis was investigated by using the systemically active mixed inhibitor of enkephalin degrading enzymes, RB 101. As already described, in both hot plate (55 +/- 0.5 degrees C) and acetic acid (0.6%) abdominal constriction tests in mice, subcutaneous administration of naloxone produced biphasic effects, with antinociceptive responses at very low doses (microgram range) and hyperalgesia at higher dose (mg range). However at concentrations producing an extracellular increase in enkephalin levels and subsequent analgesia, the mixed inhibitor prodrug of the enkephalin-metabolizing enzymes RB 101 (20 or 100 mg/kg i.v. and 5 or 10 mg/kg i.v., in the hot plate test and in the abdominal constriction test, respectively) did not potentiate the paradoxical analgesia induced by naloxone. These results are inconsistent with a negative autoregulation of endogenous enkephalin release and could suggest the involvement of the diffuse noxious inhibitory controls (DNIC). Indeed, the finding that low doses of RB 101 (1 mg/kg i.v. in the hot plate test, and 250 micrograms/kg i.v. in the abdominal constriction test) were able to induce hyperalgesic responses could indicate that the DNIC are tonically activated by endogenous enkephalins accounting for the antinociceptive responses elicited by low doses of naloxone.
Noble
F
F
Département de Pharmacochimie Moléculaire et Structurale, U266 INSERM-URA D1500 CNRS, Université René Descartes, Paris, France.
Fournié-Zaluski
M C
MC
Roques
B P
BP
D000009:Abdominal Muscles / Q000187:drug effects; D000626:Aminopeptidases / Q000037:antagonists & inhibitors; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D018826:CD13 Antigens; D004220:Disulfides / Q000494:pharmacology; D004745:Enkephalins / Q000378:metabolism*; D008297:Male; D051379:Mice; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology*; D015260:Neprilysin / Q000037:antagonists & inhibitors; D010147:Pain Measurement / Q000187:drug effects; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology
D000700:Analgesics; D004220:Disulfides; D004745:Enkephalins; C074024:RB 101; D009270:Naloxone; D010649:Phenylalanine; D000626:Aminopeptidases; D018826:CD13 Antigens; D015260:Neprilysin