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Repeated Administration of Mirtazapine Attenuates Oxaliplatin-Induced Mechanical Allodynia and Spinal NR2B Up-Regulation in Rats

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Abstract

Chemotherapic drugs may elicit acute or chronic peripheral neuropathies. Mirtazapine, as an antidepressant, is also used for the treatment of neuropathic pain. The current study aimed to investigate the effect of mirtazapine on the oxaliplatin-induced neuropathy in rats as well as the underlying mechanism. A neuropathy model was established in Sprague–Dawley rats by intraperitoneal (i.p.) injection of oxaliplatin 4 mg/kg twice a week for 4 weeks. The therapeutic potential of mirtazapine 10, 20, and 30 mg/kg/day per-orally for 28 consecutive days was evaluated. Subsequently, a dose of 1 mg/kg of WAY100635 i.p., a selective antagonist of 5-HT1A receptor, was preadministrated before mirtazapine 20 mg/kg/day per-orally in oxaliplatin-induced neuropathy. The behavioral tests and the expression of NMDA receptor subunit NR2B were determined. The results displayed that repeated administration of mirtazapine 20 or 30 mg/kg/day for 28 consecutive days significantly attenuated the mechanical allodynia and the up-regulation of spinal cord NR2B but not the cold hyperalgesia in rats with oxaliplatin-induced neuropathy, which was reversed by WAY100635 preadministration. Our findings suggest that oxaliplatin-induced mechanical allodynia is associated with spinal NR2B up-regulation, which may be attenuated by mirtazapine administration.

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References

  1. Ling B, Authier N, Balayssac D, Eschalier A, Coudore F (2007) Behavioral and pharmacological description of oxaliplatin-induced painful neuropathy in rat. Pain 128:225–234

    Article  PubMed  CAS  Google Scholar 

  2. Saif MW, Reardon J (2005) Management of oxaliplatin-induced peripheral neuropathy. Ther Clin Risk Manag 1:249–258

    PubMed  CAS  Google Scholar 

  3. Yamamoto T, Shimoyama N, Asano H, Mizuguchi T (1994) Time-dependent effect of morphine and time-independent effect of MK-801, an NMDA antagonist, on the thermal hyperesthesia induced by unilateral constriction injury to the sciatic nerve in the rat. Anesthesiology 80:1311–1319

    Article  PubMed  CAS  Google Scholar 

  4. Yamamoto T, Yaksh TL (1992) Spinal pharmacology of thermal hyperesthesia induced by constriction injury of sciatic nerve excitatory amino acid antagonists. Pain 49:121–128

    Article  PubMed  CAS  Google Scholar 

  5. Mihara Y, Egashira N, Sada H, Kawashiri T, Ushio S, Yano T, Ikesue H, Oishi R (2011) Involvement of spinal NR2B-containing NMDA receptors in oxaliplatin-induced mechanical allodynia in rats. Mol Pain 7:8

    Article  PubMed  CAS  Google Scholar 

  6. Sakurai M, Egashira N, Kawashiri T, Yano T, Ikesue H, Oishi R (2009) Oxaliplatin-induced neuropathy in the rat: involvement of oxalate in cold hyperalgesia but not mechanical allodynia. Pain 147:165–174

    Article  PubMed  CAS  Google Scholar 

  7. Gilron I, Watson CP, Cahill CM, Moulin DE (2006) Neuropathic pain: a practical guide for the clinician. Can Med Assoc J 175:265–275

    Article  Google Scholar 

  8. Max MB, Schafer SC, Culnane M, Smoller B, Dubner R, Gracely RH (1988) Amitriptyline, but not lorazepam, relieves postherpetic neuralgia. Neurology 38:1427–1432

    Article  PubMed  CAS  Google Scholar 

  9. Moulin DE, Clark AJ, Gilron I, Ware MA, Watson CP, Sessle BJ, Coderre T, Morley-Forster PK, Stinson J, Boulanger A, Peng P, Finley GA, Taenzer P, Squire P, Dion D, Cholkan A, Gilani A, Gordon A, Henry J, Jovey R, Lynch M, Mailis-Gagnon A, Panju A, Rollman GB, Velly A (2007) Pharmacological management of chronic neuropathic pain-consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag 12:13–21

    PubMed  CAS  Google Scholar 

  10. De Boer T (1996) The effects of mirtazapine on central noradrenergic and serotonergic neurotransmission. Int Clinic Psychopharmacol 10:19–23

    Article  Google Scholar 

  11. Bomholt SF, Mikkelsen JD, Blackburn-Munro G (2005) Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain. Neuropharmacology 48:252–263

    Article  PubMed  CAS  Google Scholar 

  12. Freynhagen R, Vogt J, Lipfert P, Muth-Selbach U (2006) Mirtazapine and its enantiomers differentially modulate acute thermal nociception in rats. Brain Res Bull 69:168–173

    Article  PubMed  CAS  Google Scholar 

  13. Zhu J, Wei XW, Feng XM, Song J, Hu YM, Xu JG (2008) Repeated administration of mirtazapine inhibits development of hyperalgesia/allodynia and activation of NF-κB in a rat model of neuropathic pain. Neurosci Lett 433:33–37

    Article  PubMed  CAS  Google Scholar 

  14. Schreiber S, Bleich A, Pick CG (2002) Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects—a possible opioid involvement in severe depression. J Mol Neurosci 18:143–149

    Article  PubMed  CAS  Google Scholar 

  15. Schreiber S, Rigai T, Katz Y, Pick CG (2002) The antinociceptive effect of mirtazapine in mice is mediated through serotonergic, noradrenergic and opioid mechanisms. Brain Res Bull 58:601–615

    Article  PubMed  CAS  Google Scholar 

  16. Szegedi A, Schwertfeger N (2005) Mirtazapine: a review of its clinical efficacy and tolerability. Expert Opin Pharmacother 6:631–641

    Article  PubMed  CAS  Google Scholar 

  17. Martel JC, Assié MB, Bardin L, Depoortère R, Cussac D, Newman-Tancredi A (2009) 5-HT1A receptors are involved in the effects of xaliproden on G-protein activation, neurotransmitter release and nociception. Br J Pharmacol 158:232–242

    Article  PubMed  CAS  Google Scholar 

  18. Viisanen H, Pertovaara A (2010) Roles of the rostroventromedial medulla and the spinal 5-HT1A receptor in descending antinociception induced by motor cortex stimulation in the neuropathic rat. Neurosci Lett 476:133–137

    Article  PubMed  CAS  Google Scholar 

  19. Yamamura S, Abe M, Nakagawa M, Ochi S, Ueno S, Okada M (2011) Different actions for acute and chronic administration of mirtazapine on serotonergic transmission associated with raphe nuclei and their innervation cortical regions. Neuropharmacology 60:550–560

    Article  PubMed  CAS  Google Scholar 

  20. Necker R, Hellon RF (1978) Noxious thermal input from the rat tail: modulation by descending inhibitory influences. Pain 4:231–242

    Article  PubMed  CAS  Google Scholar 

  21. Blackburn-Munro G, Bomholt SF, Erichsen HK (2004) Behavioural effects of the novel AMPA/GluR5 selective receptor antagonist NS1209 after systemic administration in animal models of experimental pain. Neuropharmacology 47:351–362

    Article  PubMed  CAS  Google Scholar 

  22. Coimbra NC, De Oliveira R, Freitas RL, Ribeiro SJ, Borelli KG, Pacagnella RC, Moreira JE, Silva LA, Melo LL, Lunardi LO, Brandão ML (2006) Neuroanatomical approaches of the tectum-reticular pathways and immunohistochemical evidence for serotonin-positive perikarya on neuronal substrates of the superior colliculus and periaqueductal gray matter involved in the elaboration of the defensive behavior and fear-induced analgesia. Exp Neurol 197:93–112

    Article  PubMed  CAS  Google Scholar 

  23. Yuen EY, Jiang Q, Chen P, Gu Z, Feng J, Yan Z (2005) Serotonin 5-HT1A receptors regulate NMDA receptor channels through a microtubule-dependent mechanism. J Neurosci 25:5488–5501

    Article  PubMed  CAS  Google Scholar 

  24. Doly S, Madeira A, Fischer J, Brisorgueil MJ, Daval G, Bernard R, Vergé D, Conrath M (2004) The 5-HT2A receptor is widely distributed in the rat spinal cord and mainly localized at the plasma membrane of postsynaptic neurons. J Comp Neurol 72:496–511

    Article  Google Scholar 

  25. Jaggi AS, Singh N (2011) Therapeutic targets for the management of peripheral nerve injury-induced neuropathic pain. CNS Neurol Disord Drug Targets 10:589–609

    Article  PubMed  CAS  Google Scholar 

  26. Thibault K, Van Steenwinckel J, Brisorgueil MJ, Fischer J, Hamon M, Calvino B, Conrath M (2008) Serotonin 5-HT2A receptor involvement and Fos expression at the spinal level in vincristine-induced neuropathy in the rat. Pain 140:305–322

    Article  PubMed  CAS  Google Scholar 

  27. Yuen EY, Jiang Q, Chen P, Feng J, Yan Z (2008) Activation of 5-HT2A/C receptors counteracts 5-HT1A regulation of N-Methyl-d-aspartate receptor channels in pyramidal neurons of prefrontal cortex. J Biol Chem 283:17194–17204

    Article  PubMed  CAS  Google Scholar 

  28. Kawashiri T, Egashira N, Kurobe K, Tsutsumi K, Yamashita Y, Ushio S, Yano T, Oishi R (2012) L type Ca2+ channel blockers prevent oxaliplatin-induced cold hyperalgesia and TRPM8 over expression in rats. Mol Pain 8:7

    Article  PubMed  CAS  Google Scholar 

  29. Deuis JR, Zimmermann K, Romanovsky AA, Possani LD, Cabot PJ, Lewis RJ, Vetter I (2013) An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1 .6 in peripheral pain pathways. Pain. doi:10.1016/j.pain.2013.05.032

  30. Durand JP, Brezatilt C, Goldwasser F (2003) Protection against oxaliplatin acute neurosensory toxicity by venlafaxine. Anticancer Drugs 14:423–425

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Mr. Genbao Feng for his excellent technical assistance and Dr. Xiaoyuan Chu for providing us oxaliplatin.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Anesthesiology, Jinling Hospital, Nanjing Clinical Medical College of the Second Military Medical University, Nanjing, 210002, China

    Xiaoyu Liu, Jinchun Shen, Weiyan Li & Jianguo Xu

  2. Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002, China

    Guangfen Zhang, Lin Dong, Xingming Wang, Heliang Sun, Jinchun Shen, Weiyan Li & Jianguo Xu

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  1. Xiaoyu Liu
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  2. Guangfen Zhang
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  3. Lin Dong
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Correspondence to Jianguo Xu.

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Liu, X., Zhang, G., Dong, L. et al. Repeated Administration of Mirtazapine Attenuates Oxaliplatin-Induced Mechanical Allodynia and Spinal NR2B Up-Regulation in Rats. Neurochem Res 38, 1973–1979 (2013). https://doi.org/10.1007/s11064-013-1103-3

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  • DOI: https://doi.org/10.1007/s11064-013-1103-3

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