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

Abstract

Rationale

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.

Objectives

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.

Methods

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.

Results

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.

Conclusions

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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References

  • Ayanwuyi LO, Carvajal F, Lerma-Cabrera JM, Domi E, Bjork K, Ubaldi M, Heilig M, Roberto M, Ciccocioppo R, Cippitelli A (2013) Role of a genetic polymorphism in the corticotropin-releasing factor receptor 1 gene in alcohol drinking and seeking behaviors of marchigian sardinian alcohol-preferring rats. Front Psychiatry 4:23

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Barbiero JK, Santiago RM, Persike DS, da Silva Fernandes MJ, Tonin FS, da Cunha C, Lucio Boschen S, Lima MM, Vital MA (2014) Neuroprotective effects of peroxisome proliferator-activated receptor alpha and gamma agonists in model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine. Behav Brain Res 274:390–399

    CAS  Article  PubMed  Google Scholar 

  • Ciccocioppo R, Sanna PP, Weiss F (2001) Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence: reversal by D(1) antagonists. Proc Natl Acad Sci U S A 98:1976–1981

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • de Guglielmo G, Cippitelli A, Somaini L, Gerra G, Li H, Stopponi S, Ubaldi M, Kallupi M, Ciccocioppo R (2013) Pregabalin reduces cocaine self-administration and relapse to cocaine seeking in the rat. Addict Biol 18:644–653

    Article  PubMed  Google Scholar 

  • de Guglielmo G, Kallupi M, Scuppa G, Stopponi S, Demopulos G, Gaitanaris G, Ciccocioppo R (2014) Analgesic tolerance to morphine is regulated by PPARgamma. Br J Pharmacol 171:5407–5416

    Article  PubMed  PubMed Central  Google Scholar 

  • de Guglielmo G, Melis M, De Luca MA, Kallupi M, Li HW, Niswender K, Giordano A, Senzacqua M, Somaini L, Cippitelli A, Gaitanaris G, Demopulos G, Damadzic R, Tapocik J, Heilig M, Ciccocioppo R (2015) PPARgamma activation attenuates opioid consumption and modulates mesolimbic dopamine transmission. Neuropsychopharmacology 40:927–937

    Article  PubMed  Google Scholar 

  • de Wit H, Stewart J (1983) Drug reinstatement of heroin-reinforced responding in the rat. Psychopharmacology 79:29–31

    Article  PubMed  Google Scholar 

  • Enomoto N, Takei Y, Hirose M, Konno A, Shibuya T, Matsuyama S, Suzuki S, Kitamura KI, Sato N (2003) Prevention of ethanol-induced liver injury in rats by an agonist of peroxisome proliferator-activated receptor-gamma, pioglitazone. J Pharmacol Exp Ther 306:846–854

    CAS  Article  PubMed  Google Scholar 

  • Festuccia WT, Oztezcan S, Laplante M, Berthiaume M, Michel C, Dohgu S, Denis RG, Brito MN, Brito NA, Miller DS, Banks WA, Bartness TJ, Richard D, Deshaies Y (2008) Peroxisome proliferator-activated receptor-gamma-mediated positive energy balance in the rat is associated with reduced sympathetic drive to adipose tissues and thyroid status. Endocrinology 149:2121–2130

    CAS  Article  PubMed  Google Scholar 

  • Fugelstad A, Stenbacka M, Leifman A, Nylander M, Thiblin I (2007) Methadone maintenance treatment: the balance between life-saving treatment and fatal poisonings. Addiction 102:406–412

    CAS  Article  PubMed  Google Scholar 

  • Gonzalez G, Oliveto A, Kosten TR (2004) Combating opiate dependence: a comparison among the available pharmacological options. Expert Opin Pharmacother 5:713–725

    CAS  Article  PubMed  Google Scholar 

  • Greenwald MK, Lundahl LH, Steinmiller CL (2013) Yohimbine increases opioid-seeking behavior in heroin-dependent, buprenorphine-maintained individuals. Psychopharmacology 225:811–824

    CAS  Article  PubMed  Google Scholar 

  • Griggs RB, Donahue RR, Morgenweck J, Grace PM, Sutton A, Watkins LR, Taylor BK (2015) Pioglitazone rapidly reduces neuropathic pain through astrocyte and nongenomic PPARgamma mechanisms. Pain 156:469–482

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Ikeda H, Taketomi S, Sugiyama Y, Shimura Y, Sohda T, Meguro K, Fujita T (1990) Effects of pioglitazone on glucose and lipid metabolism in normal and insulin resistant animals. Arzneimittelforschung 40:156–162

    CAS  PubMed  Google Scholar 

  • Kallupi M, de Guglielmo G, Cannella N, Li HW, Calo G, Guerrini R, Ubaldi M, Renger JJ, Uebele VN, Ciccocioppo R (2013) Hypothalamic neuropeptide S receptor blockade decreases discriminative cueinduced reinstatement of cocaine seeking in the rat. Psychopharmacology (Berl) 226:347–55.

  • Kreek MJ, Vocci FJ (2002) History and current status of opioid maintenance treatments: blending conference session. J Subst Abus Treat 23:93–105

    Article  Google Scholar 

  • Le AD, Harding S, Juzytsch W, Funk D, Shaham Y (2005) Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Psychopharmacology 179:366–373

    CAS  Article  PubMed  Google Scholar 

  • Maeshiba Y, Kiyota Y, Yamashita K, Yoshimura Y, Motohashi M, Tanayama S (1997) Disposition of the new antidiabetic agent pioglitazone in rats, dogs, and monkeys. Arzneimittelforschung 47:29–35

    CAS  PubMed  Google Scholar 

  • Marinelli PW, Funk D, Juzytsch W, Harding S, Rice KC, Shaham Y, Le AD (2007) The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacology 195:345–355

    CAS  Article  PubMed  Google Scholar 

  • Mello NK, Negus SS (1996) Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology 14:375–424

    CAS  Article  Google Scholar 

  • Morgenweck J, Griggs RB, Donahue RR, Zadina JE, Taylor BK (2013) PPARgamma activation blocks development and reduces established neuropathic pain in rats. Neuropharmacology 70:236–246

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • O’Brien CP (1996) Recent developments in the pharmacotherapy of substance abuse. J Consult Clin Psychol 64:677–686

    Article  PubMed  Google Scholar 

  • O’Brien C, Childress AR, Ehrman R, Robbins S, McLellan AT (1992) Conditioning mechanisms in drug dependence. Clin Neuropharmacol 15(Suppl 1 Pt A):66A–67A

    Article  PubMed  Google Scholar 

  • Park SW, Yi JH, Miranpuri G, Satriotomo I, Bowen K, Resnick DK, Vemuganti R (2007) Thiazolidinedione class of peroxisome proliferator-activated receptor gamma agonists prevents neuronal damage, motor dysfunction, myelin loss, neuropathic pain, and inflammation after spinal cord injury in adult rats. J Pharmacol Exp Ther 320:1002–1012

    CAS  Article  PubMed  Google Scholar 

  • Salehi-Sadaghiani M, Javadi-Paydar M, Gharedaghi MH, Zandieh A, Heydarpour P, Yousefzadeh-Fard Y, Dehpour AR (2012) NMDA receptor involvement in antidepressant-like effect of pioglitazone in the forced swimming test in mice. Psychopharmacology 223:345–355

    CAS  Article  PubMed  Google Scholar 

  • Sarruf DA, Yu F, Nguyen HT, Williams DL, Printz RL, Niswender KD, Schwartz MW (2009) Expression of peroxisome proliferator-activated receptor-gamma in key neuronal subsets regulating glucose metabolism and energy homeostasis. Endocrinology 150:707–712

    CAS  Article  PubMed  Google Scholar 

  • Savage SR, Kirsh KL, Passik SD (2008) Challenges in using opioids to treat pain in persons with substance use disorders. Addiction science & clinical practice 4:4–25

    Article  Google Scholar 

  • Shaham Y, Stewart J (1996) Effects of opioid and dopamine receptor antagonists on relapse induced by stress and re-exposure to heroin in rats. Psychopharmacology 125:385–391

    CAS  Article  PubMed  Google Scholar 

  • Shaham Y, Erb S, Stewart J (2000) Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res Brain Res Rev 33:13–33

    CAS  Article  PubMed  Google Scholar 

  • Shaham Y, Shalev U, Lu L, De Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168:3–20

    CAS  Article  PubMed  Google Scholar 

  • Stewart J (2003) Stress and relapse to drug seeking: studies in laboratory animals shed light on mechanisms and sources of long-term vulnerability. The American journal on addictions / American Academy of Psychiatrists in Alcoholism and Addictions 12:1–17

    CAS  Google Scholar 

  • Stewart J, Wise RA (1992) Reinstatement of heroin self-administration habits: morphine prompts and naltrexone discourages renewed responding after extinction. Psychopharmacology 108:79–84

    CAS  Article  PubMed  Google Scholar 

  • Stine SM, Southwick SM, Petrakis IL, Kosten TR, Charney DS, Krystal JH (2002) Yohimbine-induced withdrawal and anxiety symptoms in opioid-dependent patients. Biol Psychiatry 51:642–651

    CAS  Article  PubMed  Google Scholar 

  • Stopponi S, Somaini L, Cippitelli A, Cannella N, Braconi S, Kallupi M, Ruggeri B, Heilig M, Demopulos G, Gaitanaris G, Massi M, Ciccocioppo R (2011) Activation of nuclear PPARgamma receptors by the antidiabetic agent pioglitazone suppresses alcohol drinking and relapse to alcohol seeking. Biol Psychiatry 69:642–649

    CAS  Article  PubMed  Google Scholar 

  • Stotts AL, Dodrill CL, Kosten TR (2009) Opioid dependence treatment: options in pharmacotherapy. Expert Opin Pharmacother 10:1727–1740

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Strang J, Hall W, Hickman M, Bird SM (2010) Impact of supervision of methadone consumption on deaths related to methadone overdose (1993–2008): analyses using OD4 index in England and Scotland. BMJ 341:c4851

    Article  PubMed  PubMed Central  Google Scholar 

  • Umhau JC, Schwandt ML, Usala J, Geyer C, Singley E, George DT, Heilig M (2011) Pharmacologically induced alcohol craving in treatment seeking alcoholics correlates with alcoholism severity, but is insensitive to acamprosate. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 36:1178–1186

    CAS  Article  Google Scholar 

  • UNODC (2012) World Drug Report. http://www.unodc.org/unodc/en/data-and-analysis/WDR-2012.html

  • Weiss F, Ciccocioppo R, Parsons LH, Katner S, Liu X, Zorrilla EP, Valdez GR, Ben-Shahar O, Angeletti S, Richter RR (2001) Compulsive drug-seeking behavior and relapse. Neuroadaptation, stress, and conditioning factors. Ann N Y Acad Sci 937:1–26

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

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.

Ethics declarations

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). https://doi.org/10.1007/s00213-016-4452-1

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  • DOI: https://doi.org/10.1007/s00213-016-4452-1

Keywords

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