Modulation of histone deacetylase attenuates naloxone-precipitated opioid withdrawal syndrome

Ashish K. Rehni, Nirmal Singh, Mahesh Rachamalla, Kulbhushan Tikoo

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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 nalox-one (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 de-pendently attenuated naloxone-induced morphine withdrawal syndrome in vivo as well as in vitro in rat ileum. Trichostatin Awas 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.

Original languageEnglish (US)
Pages (from-to)605-619
Number of pages15
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Issue number6
StatePublished - Jun 2012
Externally publishedYes


  • Histone deacetylase
  • Interleukin-1βconverting enzyme
  • Isolated rat ileum
  • Morphine dependence
  • Withdrawal syndrome

ASJC Scopus subject areas

  • Pharmacology


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