Inhibitors of Ca(2+)-dependent endopeptidases modulate morphine-induced effects in rats

The effects of inhibitors of Ca(2+)-dependent endopeptidases (antipain and leupeptin) on morphine analgesia, reinforcing properties of morphine and on the development of opiate physical dependence were studied. Male Wistar rats were used. The analgesic action of morphine in the tail-immersion test was increased significantly by combined injection of morphine with antipain or leupeptin. Antipain or leupeptin alone had no analgesic action. The combination of morphine with antipain or leupeptin led to the reduction of morphine-induced place preference and the development of physical dependence. A single injection of antipain diminished the opiate-withdrawal signs in morphine-dependent rats. These results suggest a possible inhibitory effect of antipain or leupeptin on the Ca(2+)-dependent endopeptidases of neurons that mediate analgesia, reinforcing properties of morphine, development of opiate dependence and withdrawal.