Oxycodone withdrawal induces HDAC1/HDAC2-dependent transcriptional maladaptations in the reward pathway in a mouse model of peripheral nerve injury

Kerri D. Pryce, Randal A. Serafini, Aarthi Ramakrishnan, Andrew Nicolais, Ilinca M. Giosan, Claire Polizu, Angélica Torres-Berrío, Sreeya Vuppala, Hope Kronman, Anne Ruiz, Sevasti Gaspari, Catherine J. Peña, Farhana Sakloth, Vasiliki Mitsi, John van Duzer, Ralph Mazitschek, Matthew Jarpe, Li Shen, Eric J. Nestler, Venetia Zachariou

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The development of physical dependence and addiction disorders due to misuse of opioid analgesics is a major concern with pain therapeutics. We developed a mouse model of oxycodone exposure and subsequent withdrawal in the presence or absence of chronic neuropathic pain. Oxycodone withdrawal alone triggered robust gene expression adaptations in the nucleus accumbens, medial prefrontal cortex and ventral tegmental area, with numerous genes and pathways selectively affected by oxycodone withdrawal in mice with peripheral nerve injury. Pathway analysis predicted that histone deacetylase (HDAC) 1 is a top upstream regulator in opioid withdrawal in nucleus accumbens and medial prefrontal cortex. The novel HDAC1/HDAC2 inhibitor, Regenacy Brain Class I HDAC Inhibitor (RBC1HI), attenuated behavioral manifestations of oxycodone withdrawal, especially in mice with neuropathic pain. These findings suggest that inhibition of HDAC1/HDAC2 may provide an avenue for patients with chronic pain who are dependent on opioids to transition to non-opioid analgesics.

Original languageEnglish (US)
Pages (from-to)1229-1244
Number of pages16
JournalNature neuroscience
Volume26
Issue number7
DOIs
StatePublished - Jul 2023

All Science Journal Classification (ASJC) codes

  • General Neuroscience

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