Our preliminary findings indicate that the development of acute tolerance to opioids in certain circumstances can almost completely abolish the analgesic effect and that the development of acute tolerance may be inhibited with the combined administration of opioids and benzodiazepines. The central hypothesis in this project is that benzodiazepines can prevent the development of acute tolerance to the analgesic effect of opioids. The wide use of devices for intravenous patient-controlled postoperative analgesia and computer-assisted infusions of opioids during surgery emphasizes the importance of testing this hypothesis. We are also planning to perform an analysis of the mechanisms involved in alfentanil-midazolam interaction regarding acute tolerance to the analgesic effect. In this respect, we propose to test the following three hypothesis: 1) The effect of midazolam on the development of acute tolerance to the analgesic effect of alfentanil is not determined by pharmacokinetic factors; and 2) This effect of midazolam is mediated by benzodiazepine receptors and does not depend on direct interaction of midazolam with opioid receptors. To test the above-indicated hypotheses, we will perform experiments in rats with computer-assisted infusions of alfentanil and midazolam. Two approaches for assessment of acute tolerance to the analgesic effect of alfentanil will be used: determining the time course of analgesia with a constant blood level of alfentanil, and determining the time related changes in alfentanil requirements with a constant level of analgesia. The following basic tests will be used: reaction threshold to mechanical noxious simulation, hot-plate test, spontaneous locomotor activity, and the rotarod test. Plasma and brain concentrations of the drugs will be determined.
