Contextual control of conditioned pain tolerance and endogenous analgesic systems

  1. Sydney Trask
  2. Jeffrey S Mogil
  3. Fred J Helmstetter
  4. Cheryl L Stucky
  5. Katelyn E Sadler  Is a corresponding author
  1. Purdue University, United States
  2. McGill University, Canada
  3. University of Wisconsin-Milwaukee, United States
  4. Medical College of Wisconsin, United States

Abstract

The mechanisms underlying the transition from acute to chronic pain are unclear but may involve the persistence or strengthening of pain memories acquired in part through associative learning. Contextual cues, which comprise the environment in which events occur, were recently described as a critical regulator of pain memory; both male rodents and humans exhibit increased pain sensitivity in environments recently associated with a single painful experience. It is unknown, however, how repeated exposure to an acute painful unconditioned stimulus in a distinct context modifies pain sensitivity or the expectation of pain in that environment. To answer this question, we conditioned mice to associate distinct contexts with either repeated administration of a mild visceral pain stimulus (intraperitoneal injection of acetic acid) or vehicle injection over the course of three days. On the final day of experiments animals received either an acid injection or vehicle injection prior to being placed into both contexts. In this way, contextual control of pain sensitivity and pain expectation could be tested respectively. When re-exposed to the noxious stimulus in a familiar environment, both male and female mice exhibited context-dependent conditioned analgesia, a phenomenon mediated by endogenous opioid signaling. However, when expecting the presentation of a painful stimulus in a given context, males exhibited conditioned hypersensitivity whereas females exhibited endogenous opioid-mediated conditioned analgesia. These results are evidence that pain perception and engagement of endogenous opioid systems can be modified through their psychological association with environmental cues. Successful determination of the brain circuits involved in this sexually dimorphic anticipatory response may allow for the manipulation of pain memories, which may contribute to the development of chronic pain states.

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All data generated or analyzed during this study are included in the manuscript,

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Author details

  1. Sydney Trask

    Department of Psychological Sciences, Purdue University, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4396-5334
  2. Jeffrey S Mogil

    Department of Psychology, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Fred J Helmstetter

    Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Cheryl L Stucky

    Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4966-6594
  5. Katelyn E Sadler

    Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, United States
    For correspondence
    ksadler@mcw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2078-3527

Funding

National Institutes of Health (K99HL155791)

  • Katelyn E Sadler

National Institutes of Health (R01NS070711)

  • Cheryl L Stucky

National Institutes of Health (R37NS108278)

  • Cheryl L Stucky

Advancing a Healthier Wisconsin

  • Cheryl L Stucky

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All protocols were in accordance with National Institute of Health guidelines and were approved by the Institutional Animal Care and Use Committee at the Medical College of Wisconsin (Milwaukee, WI; protocol #0383).

Copyright

© 2022, Trask et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sydney Trask
  2. Jeffrey S Mogil
  3. Fred J Helmstetter
  4. Cheryl L Stucky
  5. Katelyn E Sadler
(2022)
Contextual control of conditioned pain tolerance and endogenous analgesic systems
eLife 11:e75283.
https://doi.org/10.7554/eLife.75283

Share this article

https://doi.org/10.7554/eLife.75283

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