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Anti-inflammatory and anti-hyperalgesic effects of milnacipran in inflamed rats: involvement of myeloperoxidase activity, cytokines and oxidative/nitrosative stress

Abstract

Background

Many injuries cause pain and inflammation, which are one of the major challenges for physicians. In this study, the analgesic and the anti-inflammatory effects of milnacipran were investigated on carrageenan-induced nociception and inflammation in male rats.

Methods

Pain and inflammation were induced by injection of λ-carrageenan (1% v/v) into the hind paw. Indomethacin (10 mg/kg: ip) or milnacipran (10, 20 and 40 mg/kg: ip) were administered 30 min before carrageenan. Analgesia and inflammation were measured by hot plate and plethysmometer. Finally, lipid peroxidation, tumor necrosis factor alpha (TNF-α), Interleukin 1 beta (IL-1β), Interleukin 6 (IL-6), myeloperoxidase (MPO) activity, nitric oxide (NO) and total antioxidant capacity (TAC) status evaluated in the hind paw tissue.

Results

The results showed that carrageenan caused hyperalgesia and inflammation in the hind paw tissue. Milnacipran (20 and 40 mg/kg) significantly and dose-dependently attenuated (65 ± 3.2%; p ≤0.01 and 42 ± 6.2%; p ≤ 0.001, respectively) carrageenan-induced inflammation and significantly increased (p ≤ 0.001) nociception threshold. Also, milnacipran (20 and 40 mg/kg) significantly suppressed levels of malondialdehyde (MDA), NO (p ≤ 0.05), MPO activity, TNF-α, IL-1β and IL-6 (p ≤ 0.001) following carrageenan injection. Additionally, milnacipran (10, 20 and 40 mg/kg) significantly augmented (p ≤ 0.05) TAC status following carrageenan in the hind paw tissue.

Conclusion

In the present study, milnacipran showed anti-nociceptive and anti-inflammatory effects on carrageenan-induced hyperalgesia and inflammation in a dose-dependent manner. Milnacipran reduced inflammatory edema and increased the paw withdrawal threshold probably through suppression of MDA, NO, TNF-α, IL-1β, IL-6 and MPO activity, and increase of TAC status in the hind paw tissue. Therefore, milnacipran holds important potential as an anti-inflammatory and anti-nociceptive drug. Although, further clinical trials to confirm this issue, is required.

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Acknowledgements

These data were adopted from the Pharm D. thesis of Dr. Rojin Rashtiani. The authors would like to thank Research and Technology Vice-Chancellor of Hamadan University of Medical Sciences (Hamadan, Iran) for supporting this study.

Funding

This work was supported by a grant from Research and Technology Vice-Chancellor of Hamadan University of Medical Sciences, Hamadan, Iran (code: 9605103034).

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RH, the supervisor of the study, was involved in concept, design, support of study, interpretation of data, drafting and final check of the draft. RR carried out the behavioral experiments, biochemical analyzes, statistical analyzes and drafting. All authors read and approved the final manuscript.

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Correspondence to Rasool Haddadi.

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Haddadi, R., Rashtiani, R. Anti-inflammatory and anti-hyperalgesic effects of milnacipran in inflamed rats: involvement of myeloperoxidase activity, cytokines and oxidative/nitrosative stress. Inflammopharmacol 28, 903–913 (2020). https://doi.org/10.1007/s10787-020-00726-2

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Keywords

  • Carrageenan
  • Milnacipran
  • Plethysmometer
  • Pain and analgesia
  • Inflammatory cytokines
  • Myeloperoxidase
  • Malondialdehyde
  • Rat