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Modulation of histone deacetylase attenuates naloxone-precipitated opioid withdrawal syndrome

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Abstract

The present study has been designed to investigate the effect of selective inhibitors of histone deacetylase and/or N-acetyl-Asp-Glu-Val-Asp-al (Ac-DEVD-CHO), a selective interleukin-1β converting enzyme inhibitor, on the development of naloxone-induced opioid withdrawal syndrome both in vitro and in vivo and the effect of histone deacetylase inhibition on histone H3 acetylation in brain. Sub-acute morphine administration followed by a single injection of naloxone (8 mg/kg, i.p.) was used to precipitate opioid withdrawal syndrome in mice. Behavioral observations were made immediately after naloxone treatment. Withdrawal syndrome was quantitatively assessed in terms of withdrawal severity score and frequency of jumping, rearing, fore paw licking and circling. Separately naloxone-induced contraction in morphine-dependent isolated rat ileum was employed as an in vitro model. An isobolographic study design was employed to assess potential synergistic activity between trichostatin A and Ac-DEVD-CHO. Brain histone acetylation status was examined by western blotting. Injection of naloxone precipitated a severe form of abstinence syndrome in morphine-dependent mice along with strong contracture in isolated rat ileum. Administration of tributyrin (1.5, 3 and 6 g/kg, p.o.), trichostatin A (0.3, 1.0 and 3.0 mg/kg, p.o.) and Ac-DEVD-CHO (0.3, 1.0 and 3.0 mg/kg, p.o.) markedly and dose dependently attenuated naloxone-induced morphine withdrawal syndrome in vivo as well as in vitro in rat ileum. Trichostatin A was also observed to exert a synergistic interaction with Ac-DEVD-CHO. Western blot analysis revealed that multiple administration with the effective dose of tributyrin or trichostatin A in the in vivo experiments induced hyperacetylation of histone H3 in the mouse brain. Thus, it is proposed that histone deacetylase activation linked mechanism might be involved in the development of opioid dependence and the precipitation of its withdrawal syndrome.

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Acknowledgements

The authors are thankful to Mr. Amteshwar Singh Jaggi, Assistant Professor, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India, for his valuable suggestions. The authors are grateful to Madhu Chitkara, General Secretary, Chitkara Educational Trust, Chandigarh, and Dr. Sandeep Arora, Director, Chitkara College of Pharmacy, Rajpura, Patiala, India, for the institutional facilities. This research was financially supported by the Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India.

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All authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, India

    Ashish K. Rehni & Nirmal Singh

  2. Laboratory of Chromatin Biology, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India

    Mahesh Rachamalla & Kulbhushan Tikoo

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  1. Ashish K. Rehni
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  2. Nirmal Singh
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Correspondence to Nirmal Singh.

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Rehni, A.K., Singh, N., Rachamalla, M. et al. Modulation of histone deacetylase attenuates naloxone-precipitated opioid withdrawal syndrome. Naunyn-Schmiedeberg's Arch Pharmacol 385, 605–619 (2012). https://doi.org/10.1007/s00210-012-0739-x

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