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Eur J Pharmacol. 2000 Nov 3;407(3):267-72.

Intrathecal Zn2+ attenuates morphine antinociception and the development of acute tolerance.

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  • 1Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Minnesota, 295 Animal Science/Veterinary Medicine Building, Saint Paul, MN 55108, USA.


Vesicular Zn2+, released in the brain and from small dorsal root ganglion neurons, interacts with opioid as well as N-methyl-D-aspartate (NMDA) receptors. We investigated the effect of Zn2+ on morphine antinociception in mice (tail flick assay), as well as acute tolerance and dependence, phenomena associated with NMDA activity. Administered intrathecally (i.t.), Zn2+ inhibited morphine antinociception in a dose-related fashion. Zn2+ also inhibited acute tolerance to morphine antinociception (5 h after 100 mg/kg of morphine). Injection i.t. of di-sodium calcium ethylenediamine tetra acetic acid (Na+Ca2+ EDTA), a chelator of divalent cations, had no effect on analgesia, acute tolerance or acute dependence. However, withdrawal jumps produced by naloxone (1 mg/kg s.c.) in morphine-pellet implanted mice (3 days) were potentiated by injections twice daily of 10 nmol of Na+Ca2+ EDTA, suggesting that endogenous Zn2+ tends to inhibit long-term development of withdrawal. These data suggest that the availability of Zn2+ is an important factor in opioid activity.

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