ArticleInterleukin-1 antagonizes morphine analgesia and underlies morphine toleranceShavit, Yehuda; Wolf, Gilly; Goshen, Inbal; Livshits, Dina; Yirmiya, Raz*Author Information Department of Psychology, The Hebrew University of Jerusalem, Mount Scopus, Jerusalem 91905, Israel *Corresponding author. Tel.: +972 2 5883695; fax: +972 2 5882947. E-mail address:[email protected] Received 29 August 2004; received in revised form 13 January 2005; accepted 7 February 2005. Pain: May 2005 - Volume 115 - Issue 1 - p 50-59 doi: 10.1016/j.pain.2005.02.003 Buy Metrics Abstract 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. © 2005 Lippincott Williams & Wilkins, Inc.