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 enkephal in release has been suggested as a possible explanation for the parado xical analgesia induced by low doses of naloxone. This hypothesis was investigated by using the systemically active mixed inhibitor of enkep halin degrading enzymes, RB 101. As already described, in both hot pla te (55 +/- 0.5 degrees C) and acetic acid (0.6%) abdominal constrictio n tests in mice, subcutaneous administration of naloxone produced biph asic effects, with antinociceptive responses at very low doses (mu g r ange) and hyperalgesia at higher doses (mg range). However at concentr ations producing an extracellular increase in enkephalin levels and su bsequent analgesia, the mixed inhibitor prodrug of the enkephalin-meta bolizing 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, respecti vely) did not potentiate the paradoxical analgesia induced by naloxone . These results are inconsistent with a negative autoregulation of end ogenous enkephalin release and could suggest the involvement of the di ffuse 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 mu g/kg i.v. in the abdominal constriction test) were able to induce hyperalge sic responses could indicate that the DNIC are tonically activated by endogenous enkephalins accounting for the antinociceptive responses el icited by low doses of naloxone.