Oxycodone Withdrawal Induces HDAC1/HDAC2-dependent Transcriptional Maladaptations in the Reward Pathway in a Mouse Model of Peripheral Nerve Injury

Overview

Journal Nat Neurosci

Date 2023 Jun 8

PMID 37291337

Authors

Kerri D Pryce

Randal A Serafini

Aarthi Ramakrishnan

Andrew Nicolais

Ilinca M Giosan

Claire Polizu

Angelica Torres-Berrio

Sreeya Vuppala

Hope Kronman

Anne Ruiz

Sevasti Gaspari

Catherine J Pena

Farhana Sakloth

Vasiliki Mitsi

John van Duzer

Ralph Mazitschek

Matthew Jarpe

Li Shen

Eric J Nestler

Venetia Zachariou

Affiliations

Soon will be listed here.

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.

Citing Articles

Converging mechanism of UM171 and KBTBD4 neomorphic cancer mutations.

Xie X, Zhang O, Yeo M, Lee C, Tao R, Harry S Nature. 2025; 639(8053):241-249.

PMID: 39939763 PMC: 11882451. DOI: 10.1038/s41586-024-08533-3.

Involvement of HDAC2-mediated kcnq2/kcnq3 genes transcription repression activated by EREG/EGFR-ERK-Runx1 signaling in bone cancer pain.

Zhang Z, Tian Y, Li S, Jing H, Cai J, Li M Cell Commun Signal. 2024; 22(1):416.

PMID: 39192337 PMC: 11350972. DOI: 10.1186/s12964-024-01797-2.

A master regulator of opioid reward in the ventral prefrontal cortex.

Smith A, Ghoshal S, Centanni S, Heyer M, Corona A, Wills L Science. 2024; 384(6700):eadn0886.

PMID: 38843332 PMC: 11323237. DOI: 10.1126/science.adn0886.

Characterization and validation of a spontaneous acute and protracted oxycodone withdrawal model in male and female mice.

Contreras K, Buzzi B, Vaughn J, Caillaud M, Altarifi A, Olszewski E Pharmacol Biochem Behav. 2024; 242:173795.

PMID: 38834159 PMC: 11283946. DOI: 10.1016/j.pbb.2024.173795.

Ginger Polyphenols Reverse Molecular Signature of Amygdala Neuroimmune Signaling and Modulate Microbiome in Male Rats with Neuropathic Pain: Evidence for Microbiota-Gut-Brain Axis.

Shen C, Santos J, Elmassry M, Bhakta V, Driver Z, Ji G Antioxidants (Basel). 2024; 13(5).

PMID: 38790607 PMC: 11118883. DOI: 10.3390/antiox13050502.

References

Darcq E, Kieffer B . Opioid receptors: drivers to addiction?. Nat Rev Neurosci. 2018; 19(8):499-514. DOI: 10.1038/s41583-018-0028-x. View

Serafini R, Pryce K, Zachariou V . The Mesolimbic Dopamine System in Chronic Pain and Associated Affective Comorbidities. Biol Psychiatry. 2019; 87(1):64-73. PMC: 6954000. DOI: 10.1016/j.biopsych.2019.10.018. View

Finnerup N, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin R . Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015; 14(2):162-73. PMC: 4493167. DOI: 10.1016/S1474-4422(14)70251-0. View

Dworkin R, OConnor A, Backonja M, Farrar J, Finnerup N, Jensen T . Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007; 132(3):237-251. DOI: 10.1016/j.pain.2007.08.033. View

Cruccu G . Treatment of painful neuropathy. Curr Opin Neurol. 2007; 20(5):531-5. DOI: 10.1097/WCO.0b013e328285dfd6. View

Hooten W, Lamer T, Twyner C . Opioid-induced hyperalgesia in community-dwelling adults with chronic pain. Pain. 2015; 156(6):1145-1152. PMC: 4431900. DOI: 10.1097/j.pain.0000000000000170. View

Volkow N, Michaelides M, Baler R . The Neuroscience of Drug Reward and Addiction. Physiol Rev. 2019; 99(4):2115-2140. PMC: 6890985. DOI: 10.1152/physrev.00014.2018. View

Zhang Y, Liang Y, Randesi M, Yuferov V, Zhao C, Kreek M . Chronic Oxycodone Self-administration Altered Reward-related Genes in the Ventral and Dorsal Striatum of C57BL/6J Mice: An RNA-seq Analysis. Neuroscience. 2018; 393:333-349. DOI: 10.1016/j.neuroscience.2018.07.032. View

Koob G, Volkow N . Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016; 3(8):760-773. PMC: 6135092. DOI: 10.1016/S2215-0366(16)00104-8. View

10.

Baliki M, Chang P, Baria A, Centeno M, Apkarian A . Resting-sate functional reorganization of the rat limbic system following neuropathic injury. Sci Rep. 2014; 4:6186. PMC: 4151103. DOI: 10.1038/srep06186. View

11.

Apkarian V, Hashmi J, Baliki M . Pain and the brain: specificity and plasticity of the brain in clinical chronic pain. Pain. 2010; 152(3 Suppl):S49-S64. PMC: 3045648. DOI: 10.1016/j.pain.2010.11.010. View

12.

Seminowicz D, Remeniuk B, Krimmel S, Smith M, Barrett F, Wulff A . Pain-related nucleus accumbens function: modulation by reward and sleep disruption. Pain. 2019; 160(5):1196-1207. PMC: 7213641. DOI: 10.1097/j.pain.0000000000001498. View

13.

Schwartz N, Temkin P, Jurado S, Lim B, Heifets B, Polepalli J . Chronic pain. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens. Science. 2014; 345(6196):535-42. PMC: 4219555. DOI: 10.1126/science.1253994. View

14.

Browne C, Godino A, Salery M, Nestler E . Epigenetic Mechanisms of Opioid Addiction. Biol Psychiatry. 2019; 87(1):22-33. PMC: 6898774. DOI: 10.1016/j.biopsych.2019.06.027. View

15.

Baliki M, Geha P, Fields H, Apkarian A . Predicting value of pain and analgesia: nucleus accumbens response to noxious stimuli changes in the presence of chronic pain. Neuron. 2010; 66(1):149-60. PMC: 2873199. DOI: 10.1016/j.neuron.2010.03.002. View

16.

Darnall B . To treat pain, study people in all their complexity. Nature. 2018; 557(7703):7. DOI: 10.1038/d41586-018-04994-5. View

17.

Bertin C, Delage N, Rolland B, Pennel L, Fatseas M, Trouvin A . Analgesic opioid use disorders in patients with chronic non-cancer pain: A holistic approach for tailored management. Neurosci Biobehav Rev. 2020; 121:160-174. DOI: 10.1016/j.neubiorev.2020.12.015. View

18.

Delorme J, Pennel L, Brousse G, Daulouede J, Delile J, Lack P . Prevalence and Characteristics of Chronic Pain in Buprenorphine and Methadone-Maintained Patients. Front Psychiatry. 2021; 12:641430. PMC: 8107279. DOI: 10.3389/fpsyt.2021.641430. View

19.

Descalzi G, Mitsi V, Purushothaman I, Gaspari S, Avrampou K, Loh Y . Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression. Sci Signal. 2017; 10(471). PMC: 5524975. DOI: 10.1126/scisignal.aaj1549. View

20.

Mitsi V, Terzi D, Purushothaman I, Manouras L, Gaspari S, Neve R . RGS9-2--controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states. Proc Natl Acad Sci U S A. 2015; 112(36):E5088-97. PMC: 4568688. DOI: 10.1073/pnas.1504283112. View