Tolerance to the antinociceptive effect of Crotalus durissus terrificus snake venom in mice is mediated by pharmacodynamic mechanisms

Crotalus durissus terrificus venom exerts central and peripheral antinocice ptive effect mediated by opioid receptors. The present work investigated th e tolerance to the antinociceptive effect of the venom and characterised th e mechanisms involved in this phenomenon. The hot plate test, applied in mi ce, was used for pain threshold determination The venom (200 mug/kg) was ad ministered by oral route, daily, for 14 days, and the nociceptive test was applied before and on days 1, 7 and 14 of the treatment. Prolonged treatmen t with venom lead to the development of tolerance to the antinociceptive ef fect. Tolerant animals exhibited increased sodium pentobarbital-induced sle eping time, although total hepatic microsomal cytochrome P450 was not alter ed. The antinociceptive effect of a single dose of venom (200 mug/kg) is me diated by kappa opioid receptors. Mice longterm-treated with venom showed c ross-tolerance to U-TRANS, an agonist of K-opioid receptor, but not to morp hine or DAMGO, two mu -opioid receptor agonists. Prolonged administration o f Venom did not cause symptoms of abstinence syndrome. These data indicate that prolonged treatment with C. durissus terrificus venom induces toleranc e to the antinociceptive effect and that pharmacodynamic mechanisms are inv olved in the genesis of this phenomenon. (C) 2001 Elsevier Science Ltd. All rights reserved.