Morphine tolerance does not develop in mice treated with endothelin-A receptor antagonists

Abstract Long-term use of morphine leads to development of antinociceptive tolerance. We provide evidence that central endothelin (ET) mechanisms are involved in development of morphine tolerance. In the present study, we investigated the effect of ET A receptor antagonists, BQ123 and BMS182874, on morphine antinociception and tolerance in mice. Mechanism of interaction of ET A receptor antagonists with morphine was investigated. BQ123 (3 μg, i.c.v.) and BMS182874 (50 μg, i.c.v.) significantly enhanced antinociceptive effect of morphine ( P A receptor antagonists did not bind directly to opioid receptors. [ 35 S]GTPγS binding was stimulated by morphine and ET-1 in non-tolerant mice. Morphine- and ET-1-induced GTP stimulation was significantly lower ( P P A antagonists promote coupling of G protein to its receptors, thereby restoring antinociceptive effect. These findings indicate that ET A receptor antagonists potentiate morphine antinociception and reverse antinociceptive tolerance in mice, through their ability to couple G proteins to opioid receptors.