Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance

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-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.

The chemokine CX3CL1/fractalkine interferes with the antinociceptive effect induced by opioid agonists in the periaqueductal grey of rats

“…It is possible that this may contribute to the results of the present study, as fractalkine-induced release of proinflammatory cytokines occurs very rapidly, in accord with the speed of effects observed here. In some reports (Johnston et al, 2004;Watkins et al, 2006;Shavit et al, 2005), IL-1 decreased the antinociceptive effects of morphine in the mice hot-plate tail-flick test and the rat thermal tail flick test. However, IL-1 has no antinociceptive effect alone nor did it affect morphine antinociception in the rat hot-plate test or in the cold-water (−3°C) tail-flick test (Adams et al, 1993).…”

Morphine enhances IL-1β release through toll-like receptor 4-mediated endocytic pathway in microglia

“…The synthesis and release of IL-1β may be mediated by some underlying cellular and molecular mechanisms [26], but the mechanisms are poorly understood. A two-signal model has been proposed to explain IL-1β synthesis and release which is a tightly controlled process.…”

Involvement of Spinal Microglial P2X7 Receptor in Generation of Tolerance to Morphine Analgesia in Rats

“…P2X 7 R has been shown to regulate the production and release of IL-1␤ and TNF␣ (Suzuki et al, 2004;Takenouchi et al, 2009). These two proinflammatory factors are potent pain mediators, and they are implicated in morphine tolerance (Shavit et al, 2005;Mika, 2008). Additionally, NMDA receptor is critically involved in the induction and maintenance of morphine tolerance (Mayer et al, 1999).…”