Abstract
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.
Footnotes
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This work was supported by a Hungarian-Spanish Scientific Research grant (17/2001), Spanish Scientific Research Council grants from Comisión Inter-ministerial de Ciencia y Tecnológica (SAF 97-0173) and Junta de Andalucía (CTS-109), and Hungarian Scientific Research grants (OTKA T-34741 and ETT 042/2001).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.103.052977.
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ABBREVIATIONS: AUC, area under the curve; ANOVA, analysis of variance.
- Received April 11, 2003.
- Accepted May 8, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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