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Pioglitazone attenuates the opioid withdrawal and vulnerability to relapse to heroin seeking in rodents



Relapse to opioids is often driven by the avoidance of the aversive states of opioid withdrawal. We recently demonstrated that activation of peroxisome proliferator-activated receptor gamma (PPARγ) by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. However, the role of PPARγ in withdrawal and other forms of relapse to heroin is unknown.


To further address this issue, we investigated the role of PPARγ on the development and expression of morphine withdrawal in mice and the effect of pioglitazone on several forms of heroin relapse in rats.


We induced physical dependence to morphine in mice by injecting morphine twice daily for 6 days. Withdrawal syndrome was precipitated on day 6 with an injection of naloxone. In addition, different groups of rats were trained to self-administer heroin and, after the extinction, the relapse was elicited by cues, priming, or stress. The effect of different doses of pioglitazone was tested on these different paradigms.


Data show that chronic and acute administration of pioglitazone attenuates morphine withdrawal symptoms, and these effects are mediated by activation of PPARγ receptors. Activation of PPARγ by pioglitazone also abolishes yohimbine-induced reinstatement of heroin seeking and reduces heroin-induced reinstatement, while it does not affect cue-induced relapse.


These findings provide new insights on the role of PPARγ on opioid dependence and suggest that pioglitazone may be useful for the treatment of opioid withdrawal in opioid-addicted individuals.

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This study was supported by the University of Camerino (to RC).

Authors contribution

GdG and RC were responsible for the study concept and design. GdG, MK, and GS contributed to the acquisition of animal data and drafted the manuscript. GD and GG provided critical revision of the manuscript for important intellectual content. All authors critically reviewed the content and approved the final version for publication.

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Correspondence to Giordano de Guglielmo or Roberto Ciccocioppo.

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All procedures were conducted in adherence with the European Community Council Directive for Care and Use of Laboratory Animals and the National Institutes of Health Guide for the Care and Use of Laboratory Animals

Conflict of interest

Dr. Demopulos is the chairman and CEO and Dr. Gaitanaris is the chief scientific officer of Omeros Corporation. Omeros exclusively controls the intellectual property rights from the University of Camerino. Dr. Ciccocioppo is the inventor on a number of patent applications, which have been assigned to Omeros, relating to the therapeutic use of PPARγ agonists in addiction. He is entitled to receive payments and royalties from Omeros under such licensing arrangement. The other authors have no conflict of interest.

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de Guglielmo, G., Kallupi, M., Scuppa, G. et al. Pioglitazone attenuates the opioid withdrawal and vulnerability to relapse to heroin seeking in rodents. Psychopharmacology 234, 223–234 (2017).

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  • Addiction
  • Heroin
  • Pioglitazone
  • Withdrawal
  • Relapse
  • Yohimbine
  • Cues
  • Priming