Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance

Yehuda Shavit, Gilly Wolf, Inbal Goshen, Dina Livshits, Raz Yirmiya*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

159 Scopus citations


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-1β 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), α-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.

Original languageAmerican English
Pages (from-to)50-59
Number of pages10
Issue number1-2
StatePublished - May 2005

Bibliographical note

Funding Information:
This work was supported by a grant from the Israel Science Foundation—The Revson Foundation (grant no. 799/03) (Y.S. and R.Y.). Facilitated by the Leon and Clara Sznajderman Chair of Psychology (Y.S.). We thank Prof. K. Iverfeldt for the IL-1raTG mice. We thank Amgen, Inc. for the generous gift of IL-1ra. Y.S. and R.Y. are members of the Hebrew University Center for Research on Pain.


  • Analgesia
  • Hyperalgesia
  • Interleukin-1
  • Interleukin-1 receptor antagonist (IL-1ra)
  • Morphine tolerance
  • Opiates


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