Role of Na,K-ATPase in Morphine-Induced Antinociception

We evaluated the modulation by Na,K-ATPase inhibitors of morphine-induced antinociception in the tail-flick test and [3H]naloxone binding to forebrain membranes. The antinoci-ception induced by morphine (1–32 mg/kg, s.c.) in mice was dose-dependently antagonized by ouabain (1–10 ng/mouse, i.c.v.), which produced a significant shift to the right of the morphine dose-response curve. The i.c.v. administration of three Na,K-ATPase inhibitors (ouabain at 0.1–100, digoxin at 1–1,000, and digitoxin at 10–10,000 ng/mouse) dose-depen-dently antagonized the antinociceptive effect of morphine (4 mg/kg, s.c.) in mice, with the following order of potency: ouabain digoxin digitoxin. This effect cannot be explained by any interaction at opioid receptors, since none of these Na,K-ATPase inhibitors displaced [3H]naloxone from it