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Peroxisome proliferator activated receptor-gamma (PPAR-γ) ligand, pioglitazone, increases analgesic and anti-inflammatory effects of naproxen

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Abstract

The aim of this study was the investigation of analgesic and anti-inflammatory activity of naproxen and pioglitazone following intra-plantar injection of carrageenan and assessment of the PPAR-γ receptor involvement in these effects. Rats were intra-plantarly injected with carrageenan (1%, 100 μl) to induce thermal hyperalgesia and paw inflammation. Different groups of rats were pre-treated intraperitoneally with naproxen (1 and 10 mg/kg) or pioglitazone (3 and 10 mg/kg) or GW9662 (a selective PPAR-γ antagonist, 100 μl/paw). The volume of the paw was evaluated using a plethysmometer, and the hot plate test was employed to assess the pain threshold in the animals. Finally, TNF-α, IL-1ß, IL-6, and myeloperoxidase (MPO) activity status were evaluated in the hind paw tissue. Naproxen and pioglitazone demonstrated analgesic and anti-inflammatory activity. Concurrent injection of an ineffective dose of naproxen (1 mg/kg) with an ineffective dose of pioglitazone (3 mg/kg) caused augmented analgesic and anti-inflammatory activity, significantly (p≤0.001 and p≤0.01, respectively). Additionally, intra-plantar injection of GW-9662 before naproxen or pioglitazone significantly suppressed their analgesic (p≤0.001) and anti-inflammatory activity (p≤0.01). Also, naproxen and pioglitazone (10 mg/kg) significantly (p≤0.001) reduced carrageenan-induced MPO activity and TNF-α, IL-6, and IL-1ß releasing. Furthermore, PPAR-γ blockade significantly prevented suppressive effects of naproxen and pioglitazone on the MPO activity and inflammatory cytokines. Pioglitazone significantly increased analgesic and anti-inflammatory effects of naproxen. This study proposes that concurrent treatment with naproxen and pioglitazone may be a substitute for overcome pain and inflammation clinically, in the future, particularly in patients with cardiovascular disorders and diabetes.

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Data availability

All datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This data was adopted from the Pharm D. thesis of Dr. Mohammad Cheraghi-poor. 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: 9604132335).

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, 6517838678, Iran

    Rasool Haddadi & Mohammad Cheraghi-poor

  2. Medicinal plant and natural products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran

    Rasool Haddadi

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  1. Rasool Haddadi
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Contributions

RH the supervisor of the study participated and was involved in the concept, design, support of the study, interpretation of data, statistical analyses, drafting, and a final check of the draft. MC doing behavioral experiments and biochemical assessment. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Rasool Haddadi.

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All procedures used in the present study were done in accordance with the National Institutes of Health ethical guidelines for the Care and Use of Laboratory Animals and approved by the University of Medical Sciences of Hamadan (UMSHA) Ethical Committee, Hamadan, Iran (ID: IR.UMSHA.REC.1396.588).

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Haddadi, R., Cheraghi-poor, M. Peroxisome proliferator activated receptor-gamma (PPAR-γ) ligand, pioglitazone, increases analgesic and anti-inflammatory effects of naproxen. Naunyn-Schmiedeberg's Arch Pharmacol 397, 1633–1646 (2024). https://doi.org/10.1007/s00210-023-02715-y

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