Histidine abolishes the inhibition by zinc of naloxone binding to opioid receptors in rat brain.
Zinc ions inhibited the specific binding of [3H]naloxone to opioid receptors in the hippocampus, cortex, midbrain and striatum of the rat in a dose-dependent manner. Scatchard analysis performed by using a concentration of zinc close to its IC50 (about 30 microM) revealed that inhibition was due to a decrease in receptor affinity, without change in the number of binding sites. Of several compounds tested, only histidine was capable of reversing the inhibition by zinc in these areas of the brain so preventing the zinc-induced increase in the KD of opioid receptors for naloxone. Histidine alone did not affect the KD or Bmax of opioid receptors for [3H] naloxone in the areas of brain studied. The fact that histidine prevented the zinc-induced increase in the KD but had no effect on receptor affinity or the number of binding sites for [3H] naloxone suggests that histidine exerts its effects by complexing with zinc ions and acting as a chelator. In addition to Zn2+, Cu2+, Cd2+ and Hg2+ inhibited the binding of [3H] naloxone to opioid receptors in the cerebral cortex of the rat in a dose-dependent manner. However, histidine was not capable of abolishing the inhibition to the same extent as that of zinc. Thus, among all of the metal ions studied, the most dramatic effect of histidine was observed with zinc ions.
Hanissian
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SH
Department of Pharmacology, College of Medicine, Ohio State University, Columbus 43210.
Tejwani
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GA
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D006632:Histamine / Q000031:analogs & derivatives / Q000494:pharmacology; D006639:Histidine / Q000494:pharmacology*; D007093:Imidazoles; D008297:Male; D009270:Naloxone / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D014131:Trace Elements / Q000494:pharmacology; D015032:Zinc / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D007093:Imidazoles; D011957:Receptors, Opioid; D014131:Trace Elements; D009270:Naloxone; D006639:Histidine; D006632:Histamine; C005954:imidazoleacetic acid; D015032:Zinc