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Neuropeptide trefoil factor 3 attenuates naloxone-precipitated withdrawal in morphine-dependent mice

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Abstract

Rationale

The persistence of physical dependence and craving in addicts is considered to contribute to relapse. Increasing evidence indicates that neuropeptide systems are associated with several phases of drug addiction, but little is known about whether the neuropeptide trefoil factor affects withdrawal symptoms.

Objectives

This study aims to investigate the potential effects of the neuropeptide trefoil factor 3 (TFF3) on naloxone-precipitated withdrawal symptoms in morphine-dependent mice.

Results

Mice received increasing doses of morphine over 3 days. On day 4, the mice were injected with TFF3 (1.0 mg/kg, i.p.) 30 min after the last dose of morphine. Thirty minutes after TFF3 treatment, naloxone (1 mg/kg, i.p.) was injected, and body weight, jumping behavior, wet-dog shakes, and locomotor activity were assessed 30 min later. Naloxone caused significant weight loss and increased jumping behavior and wet-dog shakes in morphine-dependent mice. TFF3 (1.0 mg/kg) reversed these behavioral symptoms caused by morphine withdrawal, suggesting that TFF3 might ameliorate physical dependence associated with opiate addiction. Furthermore, TFF3 pretreatment significantly reduced morphine withdrawal-induced increases in plasma corticosterone and adrenocorticotropic hormone levels. The glucocorticoid receptor agonist RU486 blocked the behavioral effects of TFF3 on morphine withdrawal symptoms. Finally, Fos expression in the medial prefrontal cortex which was decreased during morphine withdrawal was increased by TFF3 pretreatment.

Conclusion

These findings indicate that TFF3 might be a potential therapeutic candidate for opiate addiction by regulating glucocorticoid secretion and neuronal activation in the prefrontal cortex.

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Acknowledgments

This work was supported in part by the National Natural Science Foundation of China (no. 81201038, 31371140, 81201032, and 81371489), Beijing Higher Education Young Elite Teacher Project (YETP0068), Natural Science Foundation of Hebei Province (no. H2013206010), Youth Foundation of Science and Technology Studies of Hebei Province (no. Q2012078), Special Foundation from Ministry of Education of China Specialized Research Foundation for Doctoral Program of College from Ministry of National Education (no. 20121323120002), and National Science and Technology Major Project (no. 2012ZX09103-301-049, 2013ZX09103-003-012).

Conflict of interest

The authors declare that they do not have any conflicts of interest (financial or otherwise) related to the data presented in this manuscript.

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Authors and Affiliations

  1. National Institute on Drug Dependence, Peking University, 38, Xue Yuan Road, Beijing, 100191, China

    Ping Wu, Yi-Xiao Luo, Ruo-Xi Zhang, Jia-Li Li, Jie Shi, Lin Lu & Wei-Li Zhu

  2. Peking University Sixth Hospital/Institute of Mental Health, Peking University, Beijing, 100191, China

    Lin Lu

  3. Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medical University, 361, Zhongshan East Road, Shijiazhuang, 050017, China

    Hai-Shui Shi

  4. Hebei Key Laboratory of Medical Biotechnology, Hebei Medical University, Shijiazhuang, 050017, China

    Hai-Shui Shi

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  1. Ping Wu
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  2. Hai-Shui Shi
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  4. Ruo-Xi Zhang
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Correspondence to Hai-Shui Shi or Wei-Li Zhu.

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Ping Wu and Hai-Shui Shi equally contributed to this work.

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Wu, P., Shi, HS., Luo, YX. et al. Neuropeptide trefoil factor 3 attenuates naloxone-precipitated withdrawal in morphine-dependent mice. Psychopharmacology 231, 4659–4668 (2014). https://doi.org/10.1007/s00213-014-3615-1

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