Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance

Pain. 2005 May;115(1-2):50-9. doi: 10.1016/j.pain.2005.02.003.


Pain sensitivity reflects a balance between pain facilitatory and inhibitory systems. To characterize the relationships between these systems we examined the interactions between the analgesic effects of morphine and the anti-analgesic effects of the pro-inflammatory cytokine interleukin-1 (IL-1). We report that administration of a neutral dose of IL-1beta abolished morphine analgesia in mice, whereas acute or chronic blockade of IL-1 signaling by various IL-1 blockers (IL-1 receptor antagonist (IL-1ra), alpha-melanocyte-stimulating hormone, or IL-1 tri-peptide antagonist) significantly prolonged and potentiated morphine analgesia. Morphine-induced analgesia was also extended in strains of mice genetically impaired in IL-1 signaling (mice with transgenic over-expression of IL-1 receptor antagonist, deletion of the IL-1 receptor type I, or deletion of the IL-1 receptor accessory protein). The finding that IL-1 produces a marked anti-analgesic effect, suggests that it may also be involved in the development of opiate tolerance. Indeed, genetic or pharmacological blockade of IL-1 signaling prevented the development of tolerance following repeated morphine administration. Moreover, acute administration of IL-1ra in wild type mice, either immediately following the cessation of acute morphine analgesia, or following the development of chronic morphine tolerance, re-instated the analgesia, suggesting that blockade of the IL-1 system unmasks the analgesic effect of morphine. These findings suggest that morphine produces an IL-1-mediated homeostatic response, which serves to limit the duration and extent of morphine analgesia and which underlies the development of tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesia / methods*
  • Analgesics, Opioid / administration & dosage*
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Tolerance
  • Interleukin-1 / antagonists & inhibitors*
  • Interleukin-1 / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morphine / administration & dosage*
  • Pain / diagnosis
  • Pain / drug therapy*
  • Pain / metabolism*
  • Pain Threshold / drug effects*


  • Analgesics, Opioid
  • Interleukin-1
  • Morphine