|Budget Amount *help
¥2,100,000 (Direct Cost : ¥2,100,000)
Fiscal Year 1991 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1990 : ¥1,600,000 (Direct Cost : ¥1,600,000)
Opioids are known to inhibit the depolarizing action and decrease the enhanced release of neurotransmitters or intracellular substances in the central nervous system. However, the biochemical mechanism of their inhibitory action has not been elucidated so far. We previously showed that morphine stimulated the synaptic membrane (Na^++K^+)-ATPase activity suppressed by Fe^<2+>(Brain Res., 510, 92, 1990 ; J. Pharm. Pharmacol., 42, 68, 1990). In this research project, effects of subtypes of opioids on the rat synaptosomal(Na^++K^+)-ATPase activity were investigated to study the mechanisms of inhibitory action of depolarization by the opioids in the presence of several heavy metal ions. Mu agonists, morphine, morphiceptin and dynorphin A 3-8 but not the kappa agonist dynorphin-(1-8)-octapeptide, stimulated the(Na^++K^+)-ATPase activity suppressed by FeCl_2. These mu opioids, however, failed to stimulate the(Na^++K^+)-ATPase suppressed by FeCl_2 plus CuCl_2 or by other heavy metal ions teste
d(CuCl_2, CuCl, ZnCl_2, AlCl_3, BaCl_2, CdCl_2, CoCl_2, Lacl_3, PbCl_2, MnCl_2, HgCl, HgCl_2, NiCl_2, PtCl_6, RbCl, AgNO_3, V_2O_5). Mu agonists also failed to stimulate the enzyme activity suppressed by ouabain, p-chloromercuribenzoate, n-ethylmaleimide and 5, 5'-dithiobis (2-nitrobenzoic acid). When synaptic membrane were treated with copper-binding peptide, the membrane bound copper levels were significantly decreased. In these membranes, lower concentrations of FeCl_2 suppressed the (Na^++K^+)-ATPase activity and lower concentrations of mu opioids caused simulation of the enzyme activity suppressed by FeCl_2. The stimulatory effect of mu opioids was antagonized by mu receptor-specific antagonist naloxone.
These results, in conjunction with earlier data from our laboratory, suggest that mu opioid agonists may stimulate the suppressed(Na^++K^+)-ATPase activity by interacting with Fe^<2+> at mu opioid receptor sites and may inhibit the depolarization of the synaptic membranes from the cerebral cortex, and that copper may interfere with the stimulatory effect of mu agonists. Less