Advertisement

Journal of Anesthesia

, Volume 27, Issue 1, pp 93–97 | Cite as

Microglial activation involved in morphine tolerance is not mediated by toll-like receptor 4

  • Hiroshi Fukagawa
  • Tomohiro Koyama
  • Masahiro Kakuyama
  • Kazuhiko Fukuda
Original Article

Abstract

Purpose

Morphine is a powerful analgesic but its effect is often diminished owing to the development of tolerance. It has been suggested that morphine activates microglia through its action on the toll-like receptor 4 (TLR4) in the spinal cord, leading to suppression of the morphine effect. However, it has not been examined whether the development of morphine tolerance is affected by the deletion and mutation of the TLR4 gene.

Methods

Mice were treated with morphine (60 mg/kg) or vehicle once daily for five consecutive days to induce morphine tolerance, which was assessed by the tail-flick test before and after the treatment period. The effect of the microglial inhibitor minocycline, and the effect of TLR4 mutation (C3H/HeJ mouse) and deletion (TLR4-knockout mouse) on the development of morphine tolerance were tested. The expression of the microglial activation marker, CD11b, in the spinal cords of TLR4-knockout and wild-type mice after morphine treatment for 5 days was assessed by reverse-transcription polymerase chain reaction.

Results

Minocycline attenuated the development of morphine tolerance in mice. Mutation or deletion of the TLR4 gene did not significantly affect the development of morphine tolerance. CD11b mRNA expression was increased after morphine treatment both in TLR4-knockout and wild-type mice.

Conclusion

Microglial activation caused by a mechanism independent of TLR4 is involved in the development of morphine tolerance. Further studies are necessary to clarify the cellular mechanisms of morphine-induced microglial activation.

Keywords

Morphine Microglia TLR4 Minocycline 

Notes

Acknowledgments

This work was supported by a Grant-in-Aid for Exploratory Research, No. 23659742, from the Japan Society for the Promotion of Science, Tokyo, Japan.

References

  1. 1.
    Fukuda K. Opioids. In: Miller D, editor. Miller’s anesthesia. New York: Churchill Livingstone; 2009. p. 769–824.Google Scholar
  2. 2.
    Williams JT, Christie MJ, Manzoni O. Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev. 2001;81:299–343.PubMedGoogle Scholar
  3. 3.
    Habibi-Asl B, Hassanzadeh K, Charkhpour M. Central administration of minocycline and riluzole prevents morphine-induced tolerance in rats. Anesth Analg. 2009;109:936–42.PubMedCrossRefGoogle Scholar
  4. 4.
    Mika J, Wawrzczak-Bargiela A, Osikowicz M, Makuch W, Przewlocka B. Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice. Brain Behav Immun. 2009;23:75–84.PubMedCrossRefGoogle Scholar
  5. 5.
    Narita M, Suzuki M, Narita M, Niikura K, Nakamura A, Miyatake M, Yajima Y, Suzuki T. mu-Opioid receptor internalization-dependent and -independent mechanisms of the development of tolerance to mu-opioid receptor agonists: comparison between etorphine and morphine. Neuroscience. 2006;138:609–19.PubMedCrossRefGoogle Scholar
  6. 6.
    Raghavendra V, Tanga FY, DeLeo JA. Attenuation of morphine tolerance, withdrawal-induced hyperalgesia, and associated spinal inflammatory immune responses by propentofylline in rats. Neuropsychopharmacology. 2004;29:327–34.PubMedCrossRefGoogle Scholar
  7. 7.
    Hutchinson MR, Zhang Y, Shridhar M, Evans JH, Buchanan MM, Zhao TX, Slivka PF, Coats BD, Rezvani N, Wieseler J, Hughes TS, Landgraf KE, Chan S, Fong S, Phipps S, Falke JJ, Leinwand LA, Maier SF, Yin H, Rice KC, Watkins LR. Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain Behav Immun. 2010;24:83–95.PubMedCrossRefGoogle Scholar
  8. 8.
    Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282:2085–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Ogawa T, Asai Y, Hashimoto M, Takeuchi O, Kurita T, Yoshikai Y, Miyake K, Akira S. Cell activation by Porphyromonas gingivalis lipid A molecule through Toll-like receptor 4- and myeloid differentiation factor 88-dependent signaling pathway. Int Immunol. 2002;14:1325–32.PubMedCrossRefGoogle Scholar
  10. 10.
    Chen ML, Bao F, Zhang YQ, Zhao ZQ. Effects of aquaporin 4 deficiency on morphine analgesia and chronic tolerance: a study at spinal level. J Mol Neurosci. 2010;42:140–4.PubMedCrossRefGoogle Scholar
  11. 11.
    Roy A, Fung YK, Liu X, Pahan K. Up-regulation of microglial CD11b expression by nitric oxide. J Biol Chem. 2006;281:14971–80.PubMedCrossRefGoogle Scholar
  12. 12.
    Zhang Y, Li H, Li Y, Sun X, Zhu M, Hanley G, Lesage G, Yin D. Essential role of toll-like receptor 2 in morphine-induced microglia activation in mice. Neurosci Lett. 2011;489:43–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Horvath RJ, Romero-Sandoval EA, De Leo JA. Inhibition of microglial P2X4 receptors attenuates morphine tolerance, Iba1, GFAP and mu opioid receptor protein expression while enhancing perivascular microglial ED2. Pain. 2010;150:401–13.PubMedCrossRefGoogle Scholar
  14. 14.
    Zhou D, Chen ML, Zhang YQ, Zhao ZQ. Involvement of spinal microglial P2X7 receptor in generation of tolerance to morphine analgesia in rats. J Neurosci. 2010;30:8042–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev. 2011;91:461–553.PubMedCrossRefGoogle Scholar

Copyright information

© Japanese Society of Anesthesiologists 2012

Authors and Affiliations

  • Hiroshi Fukagawa
    • 1
  • Tomohiro Koyama
    • 1
  • Masahiro Kakuyama
    • 1
  • Kazuhiko Fukuda
    • 1
  1. 1.Department of AnesthesiaKyoto University HospitalKyotoJapan

Personalised recommendations