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NEUROPHARMACOLOGY

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

Department of Pharmacology and Neuroscience Institute, Faculty of Medicine, University of Granada, Granada, Spain (W.M. A.A., M.O., E.D.P., J.M.B.); and Department of Physiology, Faculties of Medicine and Health Sciences, University of Szeged, Szeged, Hungary (G.H., M.S.)

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 antinociception 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-dependently 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 its binding sites, whereas naloxone did so in a concentration-dependent manner. The antinociception induced by morphine (5 mg/kg, s.c.) in rats was antagonized by the i.c.v. administration of ouabain at 10 ng/rat, whereas it was not significantly modified by intrathecally administered ouabain (10 and 100 ng/rat). These results suggest that the activation of Na⁺,K⁺-ATPase plays a role in the supraspinal, but not spinal, antinociceptive effect of morphine.

Address correspondence to: Dr. Josè M. Baeyens, Department of Pharmacology and Neuroscience Institute, Faculty of Medicine, University of Granada, Avenida de Madrid 11, E-18012 Granada, Spain. E-mail: jbaeyens{at}ugr.es