Effect of endothelin-A receptor antagonist on mu, delta and kappa opioid receptor-mediated antinociception in mice

We have previously shown the involvement of central endothelin (ET) mechanisms in morphine analgesia and tolerance. Here we investigated the interaction of centrally administered endothelin ET(A) receptor antagonist, BMS182874, with DAMGO (micro opioid receptor agonist), SNC80 (delta opioid receptor agonist), U50,488H (kappa opioid receptor agonist), and oxycodone (micro and kappa opioid receptor agonist) towards antinociception, tolerance to antinociception and body temperature. Antinociception was determined using tail-flick latency method. BMS182874 (50microg, i.c.v.) treatment alone did not produce analgesia or change in body temperature. However, BMS182874 significantly enhanced antinociception response of DAMGO (66.75%), SNC80 (62.40%), U50,488H (55.38%), and oxycodone (61.72%). Chronic treatment with DAMGO, SNC80, U50,488H or oxycodone, induced tolerance to antinociception. Treatment with BMS182874 restored antinociceptive effect in mice that were tolerant to DAMGO, SNC80, U50,488H as well as oxycodone. Antinociceptive response of DAMGO, SNC80, U50,488H, and oxycodone in tolerant mice treated with BMS182874 was significantly higher (44.55%, 37.48%, 43.02%, and 56.08%, respectively) compared to tolerant mice treated with vehicle. Body temperature decreased with DAMGO, SNC80, U50,488H, and oxycodone; tolerance did not develop to hypothermic effect and BMS182874 did not affect DAMGO, SNC80, U50,488H, or oxycodone induced changes in body temperature. Opioid-antagonist naloxone, completely blocked antinociceptive effect of DAMGO, SNC80, U50,488H or oxycodone and potentiation of antinociception by BMS182874. It is concluded that BMS182874 potentiated antinociception and restored antinociceptive effect in mice tolerant to micro, delta and kappa selective, as well as a non-selective opioid receptor agonist. Therefore, endothelin ET(A) receptor antagonists could be useful in the restoration of antinociceptive effect during tolerance to opiates.