Intrathecal Zn2+ attenuates morphine antinociception and the development of acute tolerance.
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.
Larson
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Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Minnesota, 295 Animal Science/Veterinary Medicine Building, Saint Paul, MN 55108, USA. larso011@tc.umn.edu
Kovács
K J
KJ
Spartz
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AK
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology; D002712:Chlorides / Q000008:administration & dosage* / Q000494:pharmacology; D004347:Drug Interactions; D004361:Drug Tolerance / Q000502:physiology*; D004492:Edetic Acid / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects*; D012883:Skin Ulcer / Q000188:drug therapy*; D017967:Zinc Compounds / Q000008:administration & dosage* / Q000494:pharmacology
D000701:Analgesics, Opioid; D002614:Chelating Agents; D002712:Chlorides; D017967:Zinc Compounds; D009020:Morphine; C016837:zinc chloride; D004492:Edetic Acid