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Pioglitazone prevents morphine antinociception tolerance and withdrawal symptoms in rats

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Abstract

Long-term exposure to opiates induces tolerance to the analgesic effect and dependence. The purpose of the present study is to investigate the effects of pioglitazone, a peroxisome proliferator-activated receptors gamma (PPAR-γ) agonist, on the morphine-induced tolerance and dependence. Groups of rats received morphine in combination with a vehicle or pioglitazone (5, 10, 20, and 40 mg/kg) daily. Thirty minutes before pioglitazone (40 mg/kg), GW-9662, a selective PPAR-γ antagonist, (2 mg/kg) was administrated in order to evaluate the possible role of the PPAR-γ. Nociception was assessed by a tail flick apparatus, and the percentage of the maximal possible effect was calculated as well. For 9 days, rats received additive doses of morphine to induce dependence. Naloxone was administrated 2 h after the morphine last dose, and withdrawal symptoms were recorded for 45 min. Morphine administration to rats over a duration of 17 days resulted in the development of tolerance, whereas pioglitazone (40 mg/kg) delayed the day of the established tolerance for 15 days. Administration of pioglitazone also prevented morphine-induced 50 % effective dose (ED50) shift to the right in the dose-response curve and increased the global analgesic effect of morphine. In addition, pioglitazone decreased the total withdrawal score significantly, whereas GW-9662 significantly reversed the pioglitazone effects on the morphine tolerance and dependence. The prevention of the morphine-induced glia activation and the proinflammatory responses were the possible mechanisms for pioglitazone effect on delaying the morphine tolerance and attenuating the dependence.

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Acknowledgments

We wish to thank the Vice Chancellor’s office for Research Affairs of Tabriz University of Medical Sciences for the grant supporting this work. This article is results of thesis (No.79) submitted to the Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. We thank the reviewers of this manuscript for their helpful comments. Dr. Shahram Emami, Dr. Ali Shayanfar, Dr. Hadi Hamishehkar and Prof. Abolghasem Jouyban are gratefully acknowledged for their technical assistance

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

    Hamed Ghavimi, Nasrin Maleki-Dizaji, Alireza Azarfardian, Elmira Zolali & Mohammad Charkhpour

  2. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Hamed Ghavimi

  3. Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran

    Kambiz Hassanzadeh

  4. Department of Physiology and Pharmacology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran

    Kambiz Hassanzadeh

  5. Department of Medicinal Chemistry, School of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran

    Saeed Ghasami

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  1. Hamed Ghavimi
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Correspondence to Mohammad Charkhpour.

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Ghavimi, H., Hassanzadeh, K., Maleki-Dizaji, N. et al. Pioglitazone prevents morphine antinociception tolerance and withdrawal symptoms in rats. Naunyn-Schmiedeberg's Arch Pharmacol 387, 811–821 (2014). https://doi.org/10.1007/s00210-014-0996-y

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