The proposed research examines acute and chronic tolerance to nitrous oxide (N2O) in human subjects. In two studies, subjects will initially be trained to respond when they detect, and subsequently feel pain in response to electrical tooth stimulation. In one double-blind cross-over experiment, N2O or placebo gas will be administered for 40 min, and the detection and pain thresholds monitored. Analgesia is expected to occur in all subjects and some are hypothesized to become acutely tolerant when N2O is administered. Rebound effects will be examined when the drug is withdrawn. Degree and incidence of acute tolerance will be related to rebound effects. In a second double-blind experiment, subjects will receive N2O in association with a distinct odor cue on 5 sessions occurring over 3 days. Tolerance to the analgesic effect is hypothesized to develop over the sessions, and a final test session will determine the role that conditioning plays in the expression of this tolerance. The findings have clinical significance for those administering and taking N2O; and they have theoretical importance for understanding the mechanisms of drug tolerance and possibly addiction using a human model.
