Peroxisome proliferator-activated receptors gamma (PPARγ) modulates opioid addiction and analgesia

Pioglitazone is a selective peroxisome proliferator-activated receptor-gamma (PPARγ) agonist approved for the clinical treatment of insulin resistance and Type 2 diabetes. We recently found that activation of PPARγ by pioglitazone reduced the addictive potential of alcohol in rats. Considering the similarities between some CNS effects of alcohol and opioids we investigated the role of PPARγ on morphine and heroin pharmacology focusing on the development of analgesic tolerance and addiction. Results showed that activation of PPARγ receptors by pioglitazone selectively reduced acquisition, fixed ratio 1 and progressive ratio heroin self-administration. This effect was completely abolished by the pretreatment with the PPARγ selective antagonist GW9662. Microdialysis experiments revealed that heroin elicits a significant increase of extracellular DA levels in the NAc shell that was reduced by pioglitazone. In a rat horizontal brain slice preparation whole-cell current-clamp recordings were performed from medial posterior VTA DA neurons to further investigate the effect of pioglitazone on opioids. Acute bath application of morphine significantly increased the spontaneous activity of VTA DA neurons in a dose-dependent manner. Pre-incubation with pioglitazone dose-dependently prevented morphine-induced excitation of DA neurons. The effect of pioglitazone was blocked by bath co-application of the selective PPARγ antagonist GW9662. In the reinstatement studies pioglitazone showed anti-relapse properties by reducing yohimbine-induced and priming-induced relapse to heroin seeking and by attenuating the incubation of heroin craving. Pioglitazone also reduced the development of tolerance to the analgesic effect of morphine and the selective PPARγ antagonist GW 9662 blocked this effect. Furthermore, chronic treatment with GW 9662 alone accelerated the development of tolerance to morphine analgesia. In conditional neuronal PPARγ knockout (KO) mice we observed a faster development of tolerance to morphine analgesia compared to the wild type (WT) control mice. Moreover, in KO mice pioglitazone lost its ability to prevent the development of morphine tolerance, confirming that this effect is mediated by PPARγ. Overall, our results highlight the role of PPARγ in opioid addiction and analgesia and prompt to the possibility that pioglitazone may be useful in the treatment of opioid addiction.