Involvement of free radicals followed by the activation of phospholipase A2 in the mechanism that underlies the combined effects of methamphetamine and morphine on subacute toxicity or lethality in mice: comparison of the therapeutic potential of fullerene, mepacrine, and cooling.
An increase in polydrug abuse is a major problem worldwide. The coadministration of methamphetamine and morphine increased subacute toxicity or lethality in rodents. However, the underlying mechanisms by which lethality is increased by the coadministration of methamphetamine and morphine are not yet fully understood. Coadministered methamphetamine and morphine induced lethality by more than 80% in BALB/c mice, accompanied by the rupture of cells in the kidney and liver, and an increase in poly (ADP-ribose) polymerase (PARP)-immunoreactive cells in the heart, kidney and liver. The lethal effect and the increase in the incidence of rupture or PARP-immunoreactive cells induced by the coadministration of methamphetamine and morphine was significantly attenuated by pretreatment with mepacrine (phospholipase A(2) inhibitor) or fullerene (a radical scavenger), or by cooling from 30 to 90 min after drug administration. Furthermore, based on the results of the electron spin resonance spin-trapping technique, hydroxyl radicals were increased by the administration of methamphetamine and morphine, and these increased hydroxyl radicals were potently attenuated by fullerene and cooling. These results suggest that hydroxyl radicals plays an important role in the increased lethality induced by the coadministration of methamphetamine plus morphine. The potency of cooling or drugs for decreasing the subacute toxicity or lethality induced by the coadministration of methamphetamine and morphine was in the order fullerene=cooling>mepacrine. These results indicate that fullerene and cooling are beneficial for preventing death that is induced by the coadministration of methamphetamine and morphine.
Mori
Tomohisa
T
Department of Legal Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
Ito
Shinobu
S
Namiki
Mizuho
M
Suzuki
Tadashi
T
Kobayashi
Shizuko
S
Matsubayashi
Kenji
K
Sawaguchi
Toshiko
T
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals; D037741:Fullerenes / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D007036:Hypothermia, Induced; D013287:Illicit Drugs / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D009020:Morphine / Q000633:toxicity*; D009206:Myocardium / Q000473:pathology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D011796:Quinacrine / Q000494:pharmacology
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D005609:Free Radicals; D037741:Fullerenes; D013287:Illicit Drugs; D008694:Methamphetamine; D009020:Morphine; D010741:Phospholipases A; D054467:Phospholipases A2; D011796:Quinacrine