Induction of tolerance to crotoxin in mice

Crotoxin, the major toxic component from the venom of Crotalus durissus terrificus is a potent neurotoxin (LD50, i.p., mice, 0.09 mg/kg) which possesses phospholipase A2 activity and causes a blockade of neuromuscular transmission. In this article, we show that mice injected daily with progressively increasing doses of crotoxin develop tolerance to the lethal action of this toxin. Treated mice tolerated daily doses of crotoxin 20- to 35-fold higher than the original LD50 without the characteristic signs of toxicity. Studies on the isolated phrenic nerve-diaphragm preparation in vitro from control (crotoxin-naive) mice showed that the exposure to 2 to 10 micrograms/ml crotoxin in the bath produced complete transmission blockade in 120 to 150 min. Conversely, the preparations from crotoxin-treated mice required crotoxin concentrations in the range of 17.5 to 100 micrograms/ml to produce complete neuromuscular block, being virtually insensitive during 200 min of exposure to 5 to 10 micrograms/ml crotoxin. Phrenic nerve-diaphragm preparations of control (crotoxin-naive) and crotoxin-treated mice did not show significant differences in sensitivity to the blocking action of carbamylcholine, suggesting that induction of tolerance to crotoxin is likely a presynaptic event.