INDUCTION OF TOLERANCE TO CROTOXIN IN MICE

Crotoxin, the major toxic component from the venom of Crotalus durissu s terrificus is a potent neurotoxin (LD50, i.p., mice, 0.09 mg/kg) whi ch possesses phospholipase A2 activity and causes a blockade of neurom uscular transmission. In this article, we show that mice injected dail y with progressively increasing doses of crotoxin develop tolerance to the lethal action of this toxin. Treated mice tolerated daily doses o f crotoxin 20- to 35-fold higher than the original LD50 without the ch aracteristic signs of toxicity. Studies on the isolated phrenic nerve- diaphragm preparation in vitro from control (crotoxin-naive) mice show ed that the exposure to 2 to 10 mug/ml crotoxin in the bath produced c omplete transmission blockade in 120 to 150 min. Conversely, the prepa rations from crotoxin-treated mice required crotoxin concentrations in the range of 17.5 to 100 mug/ml to produce complete neuromuscular blo ck, being virtually insensitive during 200 min of exposure to 5 to 10 mug/ml crotoxin. Phrenic nerve-diaphragm preparations of control (crot oxin-naive) and crotoxin-treated mice did not show significant differe nces in sensitivity to the blocking action of carbamylcholine, suggest ing that induction of tolerance to crotoxin is likely a presynaptic ev ent.