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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM035135-10
Application #
2177753
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1985-09-01
Project End
1998-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
10
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Kissin, I; Brown, P T; Bradley Jr, E L (1992) Locomotor activity after recovery from hypnosis: midazolam-morphine versus midazolam. Anesth Analg 75:929-31
Kissin, I; Brown, P T; Bradley Jr, E L (1990) Morphine and fentanyl anesthetic interactions with diazepam: relative antagonism in rats. Anesth Analg 71:236-41
Kissin, I; Brown, P T; Bradley Jr, E L (1990) Sedative and hypnotic midazolam-morphine interactions in rats. Anesth Analg 71:137-43
Kissin, I; Vinik, H R; Castillo, R et al. (1990) Alfentanil potentiates midazolam-induced unconsciousness in subanalgesic doses. Anesth Analg 71:65-9
Kissin, I; Brown, P T; Bradley Jr, E L et al. (1989) Diazepam--morphine hypnotic synergism in rats. Anesthesiology 70:689-94
Kissin, I; Mason 3rd, J O; Bradley Jr, E L (1987) Morphine and fentanyl hypnotic interactions with thiopental. Anesthesiology 67:331-5
Kissin, I; Mason 3rd, J O; Bradley Jr, E L (1986) Morphine and fentanyl interactions with thiopental in relation to movement response to noxious stimulation. Anesth Analg 65:1149-54