A pilot study showing that repeated exposure to stress produces alterations in subsequent responses to anesthetics in rats

PLoS One. 2019 Mar 25;14(3):e0214093. doi: 10.1371/journal.pone.0214093. eCollection 2019.


The repeated use of a drug frequently leads to alterations in the response to that drug. We undertook this study to determine whether multiple exposures to the general anesthetic produced alterations in subsequent exposures to this anesthetic. For this study, adult male rats were anesthetized with 2.5% isoflurane for one hour. The rats were divided into 4 groups of 8 rats each. Groups 1-3 were transported between their homeroom and the anesthesia testing room and were handled in an identical manner weekly for a period of 12 weeks, but were anesthetized on different schedules. Group 1 was anesthetized weekly for 12 weeks, Group 2 on either a 3 or 4 week schedule and Group 3 was anesthetized a single time, at the end of the 12 week period. To receive anesthesia multiple times, animals were transported from their homeroom to the anesthesia location and handled repeatedly. We took into consideration of the frequency of anesthesia exposure and the stress involved. Rats in groups 2 and 3 were placed in the anesthesia chamber, with O2 but with no anesthetic, every week when they were not scheduled to receive anesthesia. In Group 4, rats were not transported or handled in any way and stayed in the home room for a period of 12 weeks. Rats in this group were anesthetized once, at the very end of the study. Recovery of the rat's righting reflex was used to assess the acceleration of recovery time from general anesthesia. Group 1 rats showed dramatically faster emergence from anesthesia after several rounds of anesthesia. Surprisingly, Groups 2 and 3 rats, treated in an identical manner as Group 1, but which were anesthetized on different schedules, also exhibited more rapid emergence from anesthesia, when compared to Group 4 rats, which were never handled or transported prior to a single anesthesia. These results suggest that the stress of transportation and handling altered responsiveness to anesthesia. Our results show that responsiveness to anesthetic agents can change over time outside of the normal developmental changes taking place in rats as they age.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthesia, General*
  • Anesthetics, Inhalation / adverse effects*
  • Anesthetics, Inhalation / pharmacology
  • Animals
  • Isoflurane / adverse effects*
  • Isoflurane / pharmacology
  • Pilot Projects
  • Rats
  • Rats, Sprague-Dawley
  • Stress, Psychological / pathology
  • Stress, Psychological / physiopathology*


  • Anesthetics, Inhalation
  • Isoflurane