In the initial project (85-88), we demonstrated that a combination of intravenous anesthetics may provide different outcomes (addition, synergism, or antagonism) regarding different components of anesthesia (e.g., unconsciousness or immobility to noxious stimulation). This was based on the suggestion that the spectrum of effects that constitutes the state of general anesthesia should not be regarded as several components of anesthesia resulting from one anesthetic action, but as separate pharmacologic actions, even if the anesthesia is produced by one drug. The primary aim of the project's continuation is to demonstrate that acute tolerance to intravenous anesthetics can be differential for various components of anesthesia. We will concentrate on the three most important components of anesthesia: analgesia, hypnosis, and immobility in response to a noxious stimulus. We will continue to analyze the role of tolerance in analgesic component of anesthesia with opioids.
Specific aims for this segment of the project are to determine: (1) which of the potential mechanisms suggested for the development of chronic tolerance to opioids (NMDA-NO system, cholecystokinin system, hyperalgesic kappa opioid system, protein kinase C system) are involved in the development of acute tolerance to the analgesic effect of alfentanil; (2) if a tonic nociceptive input suppresses the development of acute tolerance to the analgesic effect of alfentanil; (3) and if acute tolerance to the antinociceptive effect of alfentanil decreases analgesic response to alpha-2 adrenergic receptor agonists. We will also test the hypothesis that acute tolerance to thiopental develops to a different degree for hypnosis and immobility to noxious stimulation. Finally, we will test the hypothesis that the combined administration of thiopental and alfentanil results in inhibition of acute tolerance to the hypnotic effects, and that this inhibition is one of the important mechanisms of the thiopental-alfentanil hypnotic synergism. To test the above-indicated hypotheses, we will perform experiments in rats using behavioral methods of assessment of various components of anesthesia and will correlate behavioral endpoints with the plasma and brain concentrations of alfentanil and/or thiopental used for anesthesia induction and maintenance.
