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

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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. Copyright (C) 2000 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)267-272
Number of pages6
JournalEuropean Journal of Pharmacology
Issue number3
StatePublished - Nov 3 2000

Bibliographical note

Funding Information:
Supported by US Public Health Service Grants DA07234 (K.J.K.) and DA04090 (A.A.L.) from the National Institute on Drug Abuse and NS39740 (A.A.L.) from the National Institute of Neurological Disorders and Stroke and the National Institutes on Arthritis and Musculoskeletal and Skin Diseases. Also funded by an Undergraduate Research Opportunities Program Grant (A.K.S.) from the University of Minnesota.


  • Antinociception
  • Dependence
  • Intrathecal
  • Morphine
  • Tolerance
  • Zn


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