Modification of Antiallodynic and Antinociceptive Effects of Morphine by Peripheral and Central Action of Fluoxetine in a Neuropathic Mice Model


We have previously reported that serotonin concentration was reduced in the brain of mice with neuropathic pain and that it may be related to reduction of morphine analgesic effects. To further prove this pharmacological action, we applied fluoxetine, a selective serotonin reuptake inhibitor, to determine whether it suppressed neuropathic pain and examined how its different administration routes would affect antinociceptive and antiallodynic effects of morphine in diabetic (DM) and sciatic nerve ligation (SL) mice, as models of neuropathic pain. Antiallodynia and antinociceptive effect of drugs were measured by using von Frey filament and tail pinch tests, respectively. Fluoxetine given alone, intracerebroventicularly (i.c.v., 15 ώg/mouse) or intraperitoneally (i.p., 5 and 10 mg/kg) did not produce any effect in either model. However, fluoxetine given i.p. enhanced both antiallodynic and antinociceptive effects of morphine. Administration of fluoxetine i.c.v., slightly enhanced only the antiallodynic effect of morphine in SL mice. Ketanserine, a serotonin 2A receptor antagonist (i.p., 1 mg/kg) and naloxone, an opioid receptor antagonist (i.p., 3 mg/kg), blocked the combined antinociceptive effect of fluoxetine and morphine. Our data show that fluoxetine itself lacks antinociceptive properties in the two neuropathy models, but it enhances the analgesic effect of morphine in the periphery and suggests that co-administration of morphine with fluoxetine may have therapeutic potential in treatment of neuropathic pain.


  1. 1.

    Abi-Saab, W. M., Bubser, M., Roth, R. H., Deutch, A. Y. (1999) 5-HT2 receptor regulation of extracellular GABA levels in the prefrontal cortex. Neuropsychopharmacology 20, 92–96.

    CAS  Article  Google Scholar 

  2. 2.

    Arner, S., Meyerson, B. A. (1988) Lack of analgesic effect on neuropathic and idiopathic forms of pain. Pain 33, 11–23.

    CAS  Article  Google Scholar 

  3. 3.

    Cardenas, C. G., DelMar, L. P., Scroggs, R. S. (1997) Two parallel signaling pathways couple 5-HT2A receptors to N- and l-type calcium channels in C-like rat dorsal root ganglion cells. J. Neurophysiol. 77, 3284–3296.

    CAS  Article  Google Scholar 

  4. 4.

    Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M., Yaksh, T. L. (1994) Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods 53, 55–63.

    CAS  Article  Google Scholar 

  5. 5.

    DeGroot, J. F., Coggeshall, R. E., Carlton, S. M. (1997) The reorganization of mu opioid receptors in the rat dorsal horn following peripheral axotomy. Neurosci. Lett. 233, 113–116.

    CAS  Article  Google Scholar 

  6. 6.

    Gorlitz, B. D., Frey, H. H. (1972) Central monoamines and antinociceptive drug action. Eur. J. Pharmacol. 20, 171–180.

    CAS  Article  Google Scholar 

  7. 7.

    Gray, A. M., Spencer, P. S. J., Sewell, R. D. E. (1998) The involvement of opioidergic system in the antinociceptive mechanisms of action of antidepressant compounds. Br. J. Pharmacol. 124, 669–674.

    CAS  Article  Google Scholar 

  8. 8.

    Haley, T. J., McCormick, W. G. (1957) Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse. Br. J. Pharmacol 12, 12–15.

    CAS  Google Scholar 

  9. 9.

    Iadarola, M. J., Caudle, R. M. (1997) Neuroscience: good pain, bad pain. Science 278, 239–240.

    CAS  Article  Google Scholar 

  10. 10.

    Malmberg, A. B., Basbaum, A. I. (1998) Partial sciatic nerve injury in the mouse as amodel of neuropathic pain: behavioral and neuroanatomical correlates. Pain 76, 215–222.

    CAS  Article  Google Scholar 

  11. 11.

    Nestler, E. J., Hyman, S. E., Malenka, R. C. (2001) Serotonin, Acetylcholine and Histamine. Molecular Neuropharmacology, a Foundation for Clinical Neuroscience. McGraw-Hill, pp. 191–200.

    Google Scholar 

  12. 12.

    Rita, B. M., Loy, D. L. (1977) Serotonin containing neurons: their possible role in pain and analgesia. Pain 4, 1–21.

    Article  Google Scholar 

  13. 13.

    Sastre, C. A., Esteban, S., Garcia, S. J. A. (2002) Supersensitivity of 5-HT1A autoreceptors and alpha2-adrenoceptors regulating monoamine synthesis in the brain of morphine-dependence rats. Naunyn Schmiedebergs Arch. Pharmacol. 365, 210–219.

    Article  Google Scholar 

  14. 14.

    Sierralta, F., Pinardi, G., Medez, M., Miranda, H. F. (1995) Interaction of opioids with antidepressant-induced antinociception. Psychopharmacology 122, 374–378.

    CAS  Article  Google Scholar 

  15. 15.

    Sounvoravong, S., Nakashima, N. M., Wada, M., Nakashima, K. (2004) Decrease in serotonin concentration in raphe magnus nucleus and attenuation of morphine analgesia in two mice models of neuropathic pain. Eur. J. Pharmacol. 484, 217–223.

    CAS  Article  Google Scholar 

  16. 16.

    Sounvoravong, S., Nakashima, N. M., Wada, M., Nakashima, K. (2004) Disability of development of tolerance to morphine and U-50,488H, a selective kappa-opioid receptor agonist, in neuropathic pain model mice. J. Pharmacol. Sci. 94, 305–312.

    CAS  Article  Google Scholar 

  17. 17.

    Takagi, H., Inukai, T., Nakama, M. (1966) A modification of Haffner’s method for testing analgesics. Jpn. J. Pharmacol. 16, 287–294.

    CAS  Article  Google Scholar 

  18. 18.

    Todorovic, S. M., Scroggs, R. S., Anderson, E. G. (1997) Cationic modulation of 5-HT2 and 5-HT3 receptors in rat sensory neurons: the role of K+, Ca2+ and Mg2+, Ca2+ and Mg2+. Brain Res. 765, 291–300.

    CAS  Article  Google Scholar 

  19. 19.

    Tokunaga, A., Saika, M., Senba, E. (1998) 5-HT2A receptor subtype is involved in the thermal hyperalgesic mechanism of serotonin in the periphery. Pain 76, 349–355.

    CAS  Article  Google Scholar 

  20. 20.

    Vijay, P. S., Naveen, K. J., Kulkarni, S. K. (2001) On the antinociceptive effect of fluoxetine, a selective serotonin reuptake inhibitor. Brain Res. 915, 218–226.

    Article  Google Scholar 

  21. 21.

    Virginia, M. G., Yan, H., Kevin, V. H., Robert, L. S. J. (2002) Reduced basal release of serotonin from the ventrobasal thalamus of the rat in a model of neuropathic pain. Pain 99, 359–366.

    Article  Google Scholar 

  22. 22.

    Zhang, Y. Q., Gao, X., Huang, Y. L., Wu, G. C. (2000a) Expression of 5-HT1A receptor mRNA in rat dorsal raphe nucleus and ventrolateral periaqueductal gray neurons after peripheral inflammation. Neuroreport 11, 3361–3365.

    CAS  PubMed  Google Scholar 

  23. 23.

    Zhang, Y. Q., Gao, X., Yang, Z. L., Huang, Y. L., Wu, G. C. (2000b) Expression of 5-HT1A receptor mRNA in rat nucleus raphe magnus neurons after peripheral inflammation. Brain Res. 887, 465–468.

    Article  Google Scholar 

  24. 24.

    Zhang, Y. Q., Gao, X., Zhang, L. M., Wu, G. C. (2000c) The release of serotonin in rat spinal dorsal horn and periaqueductal gray following carrageenan inflammation. Neuroreport 11, 3539–3543.

    CAS  Article  Google Scholar 

Download references


The authors acknowledge the support provided by the Tokyo Biochemical Research Foundation. The authors also would like to thank Dr. Gwyn A Lord, University of London, for revising the manuscript and helpful suggestions.

Author information



Corresponding author

Correspondence to K. Nakashima.

Rights and permissions

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Reprints and Permissions

About this article

Cite this article

Sounvoravong, S., Nakashima, M.N., Wada, M. et al. Modification of Antiallodynic and Antinociceptive Effects of Morphine by Peripheral and Central Action of Fluoxetine in a Neuropathic Mice Model. BIOLOGIA FUTURA 58, 369–379 (2007).

Download citation


  • Neuropathic pain
  • serotonin
  • morphine
  • fluoxetine