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.