Long-lasting antinociceptive effect of DAMGO chloromethyl ketone in rats

Previously, the opioid peptide Tyr-D-Ala-Gly-(NMe)Phe-CH2Cl (DAMCK) has bee n shown to bind irreversibly to mu opioid receptors in vitro. In the presen t work, the antinociceptive effect of DAMCK has been evaluated. Rats treate d systemically with DAMCK (1-100 pg/kg) displayed a dose-dependent increase in tail-flick analgesia that peaked by 15 min, then stayed about the same until 60 min, followed by some decrease over time. Higher doses of DAMCK (1 0 ng/kg-100 mu g/kg) produced a near-maximal antinociceptive effect that re mained stable for 4 h. Significant antinociception was still detected 8 h, but not 24 h postinjection. In comparison, the parent peptide DAMGO (Tyr-D- Ala-Gly-(NMe)Phe-Gly-ol) reached maximal effect by about 30 min, followed b y a rapid cessation of its antinociceptive response. Naloxone administered before DAMCK antagonized the antinociceptive response of DAMCK, indicating that it was mediated via opioid receptors. Naloxone administered 45 min aft er DAMCK attenuated the tail-flick response to some extent, but a substanti al part (40-60% depending on the peptide concentration and evaluation time) remained unaffected. Central administration of DAMCK also elicited time- a nd concentration-dependent, profound, opioid receptor mediated, apparently irreversible antinociception. (C) 1999 Elsevier Science Inc. All rights res erved.