Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance.
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.
Shavit
Yehuda
Y
Department of Psychology, The Hebrew University of Jerusalem, Mount Scopus, Jerusalem 91905, Israel.
Wolf
Gilly
G
Goshen
Inbal
I
Livshits
Dina
D
Yirmiya
Raz
R
D000698:Analgesia / Q000379:methods*; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage*; D010146:Pain / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects*
D000701:Analgesics, Opioid; D007375:Interleukin-1; D009020:Morphine