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To test the role of cholecystokinin (CCK) and N-methyl-d-aspartate-nitric oxide (NMDA-NO) systems in the development of acute tolerance to analgesia during alfentanil IV infusion, we conducted experiments in rats with the use of an infusion algorithm designed to maintain a constant plasma level of the opioid for 4 h. The degree of acute tolerance was determined on the basis of decline in the level of analgesia measured with a tail compression test. CCKB receptor antagonists (proglumide, CI-988, and L-365,260) and NMDA-NO cascade inhibitors (dizocilpine and NO synthase inhibitor) were administered 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 alfentanil 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 NG-nitro-l-arginine methyl ester attenuated acute tolerance at 1 h of alfentanil infusion by approximately 65% and 65% and by the end of 4-h infusion by 30% and 0%, respectively. Comparison of the results with CCKB receptor antagonists and inhibitors of NMDA-NO cascade demonstrates that both groups of drugs provide more or less similar degrees of attenuation of acute tolerance to the antinociceptive effect of alfentanil, and none of these drugs completely prevents tolerance development.The mechanism of acute tolerance to the analgesic effect of alfentanil depends on participation of multiple systems of adaptation that include cholecystokininB receptors and N-methyl-d-aspartic acid-nitric oxide cascade. Drugs that inhibit function of these systems attenuate tolerance development.