Experimental Study on the Role of 5-Ht2 Serotonin Receptors in the Mechanism of Anti-Inflammatory and Antihyperalgesic Action of Antidepressant Fluoxetine


INTRODUCTION: Fluoxetine is an antidepressant that has anti-inflammatory and antihyperalgesic effects in experimental models of pain and inflammation. The AIM of the present study was to determine the role of 5-HT2 receptors in the mechanism of anti-inflammatory and antihyperalgesic action of fluoxetine after single and repeated administration of the drug. MATERIALS AND METHODS: 40 male Wistar rats were randomly divided in five groups (n = 8) treated for 14 days with saline (control), diclofenac (positive control), fluoxetine, cyproheptadine (5-HT2 antagonist), and fluoxetine + cyproheptadine, respectively. We used the experimental model of inflammation induced by intraplantar injection of carrageenan and nociceptive test with mechanical pressure on the inflamed hind paw. RESULTS: Single and repeated administration of fluoxetine showed that it had significant anti-inflammatory and antihyperalgesic effects when compared with the control (p < 0.05). Cyproheptadine did not change significantly the anti-inflammatory effect of fluoxetine in the first 4 hours, after a single administration. At 24 hours the combination did not differ statistically when compared with the control. Cyproheptadin did not change significantly the anti-inflammatory effect of fluoxetine after repeated administration. After prolonged treatment the group that received fluoxetine + cyproheptadine showed a statistically significant increase in paw pressure to withdraw the hind paw compared with that treated with fluoxetine alone (p < 0.05). CONCLUSIONS: Fluoxetine has anti-inflammatory and antihyperalgesic effects in the carrageenan model of inflammation. 5-HT2 receptor mediated its anti-inflammatory effect in single dose treated animals. Spinal 5-HT2 receptors are involved in the antihyperalgesic effect of fluoxetine after repeated administration

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. Sghendo L, Mifsud J. Understanding the molecular pharmacology of the serotonergic system: using fl uoxetine as a model. J Pharm Pharmacol 2012;64(3):317-25.

  • 2. Abdel-Salam OM, Baiuomy AR, Arbid MS. Studies on the anti-infl ammatory effect of fl uoxetine in the rat. Pharmacol Res 2004;49(2):119-31.

  • 3. Maes M, Yirmyia R, Noraberg J, Brene S, et al. The infl ammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis 2009;24(1):27-53.

  • 4. Altschuler EL, Kast RE. Bupropion in psoriasis and atopic dermatitis: decreased tumor necrosis factoralpha? Psychosom Med 2003;65(4):719.

  • 5. Singh VP, Jain NK, Kulkarni SK. On the antinociceptive effect of fl uoxetine, a selective serotonin reuptake inhibitor. Brain Res 2000;915(2):218-26.

  • 6. Ozdemir E, Bagcivan I, Gursoy S, Altun A, Durmus N. Effects of fl uoxetine and LY 367265 on tolerance to the analgesic effect of morphine in rats. Acta Physiol Hung 2011;98(2):205-13.

  • 7. Zhao, ZQ, Chiechio, S, Sun, YG, Zhang, KH, et al. Mice lacking central serotonergic neurons show enhanced infl ammatory pain and an impaired analgesic response to antidepressant drugs. J Neurosci 2007;27:6045-53.

  • 8. Sasaki M, Obata H, Kawahara K, Saito S, Goto F. Peripheral 5-HT2A receptor antagonism attenuates primary thermal hyperalgesia and secondary mechanical allodynia after thermal injury in rats. Pain 2006;122(1-2):130-6.

  • 9. Abdel-Salam OM, Nofal SM, El Shenawy SM. Evaluation of the anti-infl ammatory and anti-nociceptive effects of different antidepressants in the rat. Pharmacol Res 2003;48(2):157-65.

  • 10. Maleki N, Nayebi AM, Garjani A. Effects of central and peripheral depletion of serotonergic system on carrageenan-induced paw oedema. Int Immunopharmacol 2005;5(12):1723-30.

  • 11. Jorgensen HS. Studies on the neuroendocrine role of serotonin. Dan Med Bull 2007;54(4):266-88.

  • 12. Huang J, Fan Y, Jia Y, Hong Y. Antagonism of 5-HT(2A) receptors inhibits the expression of pronociceptive mediator and enhances endogenous opioid mechanism in carrageenan-induced infl ammation in rats. Eur J Pharmacol 2011;654(1):33-41.

  • 13. Sanchez C, Hyttel J. Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell Mol Neurobiol 1999;19:467-89.

  • 14. Le Bars D, Gozariu M, Cadden SW. Animal models of nociception. Pharmacol Rev 2001;53(4):597-652.

  • 15. Sasaki M, Obata H, Saito S, Goto F. Antinociception with intrathecal α-methyl-5-hydroxytryptamine, a 5-hydroxytryptamine 2A/2C receptor agonist, in two rat models of sustained pain. Anesth Analg 2003;96(4):1072-8.

  • 16. Griffi ths JL, Lovick TA. Co-localization of 5-HT2Areceptor- and GABA immunoreactivity in neurones in the periaqueductal grey matter of the rat. Neurosci Lett 2002;326(3):151-4.

  • 17. Wang YY, Wei YY, Huang J, Wang W, et al. Expression patterns of 5-HT receptor subtypes 1A and 2A on GABAergic neurons within the spinal dorsal horn of GAD67-GFP knock-in mice. J Chem Neuroanat 2009;38:75-81.

  • 18. Li H, Lang B, Kang JF, Li YQ. Serotonin potentiates the response of neurons of the superfi cial laminae of the rat spinal dorsal horn to gamma-aminobutyric acid. Brain Res Bull 2000;52(6):559-65.

  • 19. Pichon X, Wattiez AS, Becamel C, Ehrlich I, Bockaert J, Eschalier A, Marin P, Courteix C. Disrupting 5-HT(2A) receptor/PDZ protein interactions reduces hyperalgesia and enhances SSRI effi cacy in neuropathic pain. Mol Ther 2010;18(8):1462-70.


Journal + Issues