Involvement of intracellular calcium in morphine tolerance in mice

Opioid analgesic tolerance is associated with a disruption in Ca++ homeosta sis. Drugs reducing Ca++ influx can prevent and reverse tolerance. The hypo thesis was tested that both Ca++ influx and mobilization from intracellular pools maintains the expression of morphine tolerance. Ca++ modulating drug s were injected ICV at doses not affecting morphine's potency in placebo pe llet-implanted mice, in order to determine whether tolerance would be rever sed in morphine pellet-implanted mice. The Ca++ chelator EGTA significantly reversed tolerance. The Ca++ channel antagonists nifedipine and omega-cono toxin GVIA also reversed tolerance. The role of intracellular Ca++ was inve stigated using the membrane permeable intracellular Ca++ chelator EGTA-AM. EGTA-AM reversed tolerance at lower morphine doses, but not at higher morph ine doses. Thus, mobilization of intracellular Ca++ contributes to the expr ession of tolerance. Finally, 1,4-dihydropyridine-sensitive Ca++ channels a re known to stimulate Ca++-induced Ca++ release (CICR) from Ca++/caffeine-s ensitive microsomal pools possessing ryanodine receptors. We examined wheth er blocking Ca++ mobilization from these pools with ryanodine would reverse morphine tolerance. Ryanodine's effects were similar to EGTA-AM. Tolerance was reversed at lower morphine doses, but not at higher doses. Thus, morph ine tolerance appears to be associated with increases in Ca++ influx and mo bilization from Ca++/cafieine-sensitive pools. (C) 1999 Elsevier Science In c.