Acute tolerance to continuously infused alfentanil: The role of cholecystokinin and N-methyl-D-aspartate-nitric oxide systems

To test the role of cholecystokinin (CCK) and N-methyl-D-aspartate-nitric o xide (NMDA-NO) systems in the development of acute tolerance to analgesia d uring alfentanil IV infusion, we conducted experiments in rats with the use of an infusion algorithm designed to maintain a constant plasma level of t he opioid for 4 h. The degree of acute tolerance was determined on the basi s of decline in the level of analgesia measured with a tail compression tes t. CCK, receptor antagonists (proglumide, CI-988, and L-365,260) and NMDA-N O cascade inhibitors (dizocilpine and NO synthase inhibitor) were administe red before the start of alfentanil infusion. Use of 30 mg/kg proglumide, 10 mg/kg CI-988, and 1 mg/kg L-365,260 attenuated acute tolerance at 1 h of a lfentanil infusion by approximately 60%, 55%, and 70%, respectively, and by the end of 4-h infusion by 50%, 50%, and 25%, respectively. Use of 0.1 mg/ kg dizocilpine and 10 mg/kg N-G-nitro-L-arginine methyl ester attenuated ac ute tolerance at 1 h of alfentanil infusion by approximately 65% and 65% an d by the end of 4-h infusion by 30% and 0%, respectively. Comparison of the results with CCK, receptor antagonists and inhibitors of NMDA-NO cascade d emonstrates that both groups of drugs provide more or less similar degrees of attenuation of acute tolerance to the antinociceptive effect of alfentan il, and none of these drugs completely prevents tolerance development.