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

Nature Neuroscience volume 26, pages 1229–1244 (2023)Cite this article

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An Author Correction to this article was published on 22 January 2024

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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.

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Fig. 1: Chronic oxycodone exposure and spontaneous oxycodone withdrawal produce weight loss and sensory deficits in long-term spared nerve injury and pain-free mice.
Fig. 2: Oxycodone withdrawal alters emotional and social behaviors.
Fig. 3: Oxycodone withdrawal alters broad transcriptome patterns in brain reward regions of chronic neuropathic pain and pain-free mice.
Fig. 4: Predicted biological processes and transcriptional regulators altered by oxycodone withdrawal with chronic neuropathic pain and pain-free states.
Fig. 5: Transcriptomic effects of oxycodone withdrawal are differentially expressed across reward-related brain regions with chronic SNI and Sham states.
Fig. 6: Pharmacological inhibition of HDAC1/HDAC2 using RBC1HI ameliorates sensory hypersensitivity signs of opioid withdrawal.
Fig. 7: RBC1HI treatment reverses affective symptoms of oxycodone withdrawal.

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Data availability

RNA-seq data are available on the NCBI Gene Expression Omnibus under accession GSE223541. Other data from this study can be made available upon request.

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Acknowledgements

This study was supported by National Institute of Neurological Disorders and Stroke NS086444 (to V.Z.), R01 NS111351, (to V.Z.), R01NS086444S1 (to R.S.) and National Institute on Drug Abuse P01 DA047233 (to E.J.N. and V.Z.), T32 5T32DA007135-34 (to K.D.P.) and R01NS08644S1 (to K.D.P).

Author information

Author notes

  1. Ilinca M. Giosan & Venetia Zachariou

    Present address: Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA

  2. These authors contributed equally: Kerri D. Pryce, Randal Serafini.

Authors and Affiliations

  1. Nash Family Department of Neuroscience, Department of Pharmacological Sciences, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    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, Farhana Sakloth, Vasiliki Mitsi, Li Shen, Eric J. Nestler & Venetia Zachariou

  2. Princeton Neuroscience Institute, Princeton, NJ, USA

    Catherine J. Peña

  3. Acetylon Pharmaceuticals, Waltham, MA, USA

    John van Duzer

  4. Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA

    Ralph Mazitschek

  5. Regenacy Pharmaceuticals, Waltham, MA, USA

    Matthew Jarpe

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Contributions

K.D.P. and R.S. performed experiments, experimental design, data analysis, statistical analysis, manuscript writing and editing; A.R., L.S. and C.P. performed bioinformatic analysis, writing and editing; C.P., V.M., A.T.-B., F.S., A.N., I.G., K.D.P. and R.S. contributed to behavioral experiments; H.K., A.R., R.S., S.V., S.G. and C.J.P. contributed to biochemical experiments and manuscript editing; R.M., J.v.D. and M.J. provided HDAC inhibitors, biochemical analysis and manuscript editing; L.S. and E.N. rigorously revised the manuscript; V.Z. contributed to experimental design and writing and editing the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Venetia Zachariou.

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Competing interests

The authors declare no competing interests. V.Z. and K.D.P. are inventors on a provisional patent regarding RBC1HI as part of an agreement between the Icahn School of Medicine at Mount Sinai and Regenacy Pharmaceuticals.

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Nature Neuroscience thanks Theodore Price and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Additional affective behavior assays after oxycodone withdrawal with or without SNI.

a. No significant difference was observed in the open-field assay (Sham-Sal n = 8, Sham-Oxy n = 9, SNI-Sal n = 8, SNI-Oxy n = 10). b. The time spent in the open arm of the elevated plus maze was significantly increased with oxycodone withdrawal in SNI animals when compared with Sham animals (Sham-Sal n = 9, Sham-Oxy n = 9, SNI-Sal n = 9, SNI-Oxy n = 8; two-way ANOVA interaction F1,31 = 6.299, p = 0.0175; Sidak’s multiple comparisons Oxy SNI vs Sham t = 3.62, df=31, p = 0.0021). c. No significant difference was observed in the nest building assay (Sham-Sal n = 13, Sham-Oxy n = 16, SNI-Sal n = 12, SNI-Oxy n = 14). d. Latency to eat in a novel environment after food deprivation was significantly affected in Sham-Oxy, SNI-Sal, and SNI-Oxy groups as compared with the Sham-Sal controls (Sham-Sal n = 13, Sham-Oxy n = 14, SNI-Sal n = 18, SNI-Oxy n = 15; two-way ANOVA interaction F1,56 = 6.052, p = 0.0170; Sidak’s m.c. SNI-Sal vs Sham-Sal t = 2.963, df=56, p = 0.0089; Sham-Oxy vs Sham-Sal t = 3.249, df=56, p = 0.0039; Tukey’s m.c. SNI-Oxy vs Sham-Sal q = 3.92, df=56, p = 0.0369). e. Total distance traveled during the NSF assay was significantly affected by oxycodone withdrawal in SNI-Oxy and Sham-Oxy (Sham-Sal n = 14, Sham-Oxy n = 13, SNI-Sal n = 12, SNI-Oxy n = 13; two-way ANOVA treatment F1,48 = 20.45, P < 0.001; Sidak’s m.c. Sham-Oxy vs Sham-Sal t = 2.88, df=48, p = 0.0118; SNI-Oxy vs SNI-Sal t = 3.505, df=48, p = 0.002). Values are represented as mean ± SEM *p < 0.05 and ** p < 0.001respectively.

Extended Data Fig. 2 NAc RNA-seq deconvolution across injury and withdrawal conditions.

a–c. RNA-seq deconvolution of Sham-Oxy vs Sham-Saline, SNI-Saline vs Sham Saline, and SNI-Oxy vs Sham-Saline, respectively (n = 4 per group), demonstrating condition-specific alterations in transcriptomic representations of neuronal and vascular cell subtypes (Sham-Oxy vs Sham-Sal Neuron_1 unpaired t-test, t = 2.595, df=6, p = 0.0409; SNI-Sal vs Sham-Sal Mural unpaired t-test, t = 2.456, df=6, p = 0.0494, Neuron_1 unpaired t-test, t = 2.042, df=6, p = 0.0873, Microglia Welch’s unpaired t-test, t = 2.818, df=3.328, p = 0.0593; SNI-Oxy vs Sham-Sal unpaired t-test, t = 2.025, df=6, p = 0.0893). Values are represented as mean ± SEM *p < 0.05.

Extended Data Fig. 3 mPFC and NAc HDAC1 expression in neuronal and glial cells.

a, b. Immunofluorescence staining of HDAC1 in the mPFC and NAc demonstrating high protein nuclear presence across most cells in these regions (naïve mice, n = 3 per group). c, d. RNAscope imaging of Hdac1 transcript colocalization with Tubb3, a pan-neuronal marker, in the mPFC and NAc, demonstrating neuronal expression. e, f. RNAscope imaging of Hdac1 transcript colocalization with Aif1, a microglial marker, demonstrating microglial expression.

Extended Data Fig. 4 Pharmacological and in vivo characterizations of RBC1HI.

a. Molecular structure of RBC1HI. b. RBC1HI enzymatic inhibition of HDAC1,2,3 (‘HDAC3’=free versus HDAC3 bound to NCOR2) demonstrating highest specificity to HDAC1 (n = 3 replicates; (AUC one-way ANOVA: F3,8 = 191.1, p < 0.0001; Tukey’s m.c. HDAC1 vs HDAC2 q = 11.55, df=8, p = 0.0002; HDAC1 vs free HDAC3 q = 17.22, df=8, p < 0.0001; HDAC1 vs HDAC3/NCOR2 q = 16.21, df=8, p < 0.0001; HDAC2 vs free HDAC3 q = 17.22, df=8, p < 0.0001; HDAC2 vs HDAC3/NCOR2 q = 16.21, df=8, p < 0.0001). c. Plasma bioavailability of RBC1HI at 3 or 10 mg/kg and with intraperitoneal versus oral administration, demonstrating longer bioavailability with the intraperitoneal route. d. Brain bioavailability of RBC1HI with the aforementioned administration doses and routes, demonstrating prolonged drug presence with the intraperitoneal route. Brain to plasma concentration ratios over time. Dose-dependent circulating RBC1HI bioavailability as measured by plasma concentration and brain concentration over time (3 mg/kg i.p.; n = 3 male C57BL/6 mice per time point). e. RBC1HI (3 mg/kg intraperitoneal) did not promote place preference as seen with morphine (6 mg/kg subcutaneous; paired t-test, t = 7.326, d.f. = 4, P = 0.0018). f. 3 mg/kg RBC1HI does not affect locomotor activity up to two hours after administration. Values are represented as mean ± SEM **P < 0.01, ****p < 0.0001.

Extended Data Fig. 5 Additional affective behaviors after treatment with RBC1HI.

a. Habituation phase of Sham-Sal male mice after receiving Veh or RBC1HI, demonstrating equal interaction times for two empty cups (Sham-Sal-Veh n = 9, Sham-Sal-RBC1HI n = 10). b. RBC1HI and Veh animals both showed a preference for social targets in the sociability phase of the social interaction assay (Sham-Sal-Veh n = 8, Sham-Sal-RBC1HI n = 9). c. Female mice undergoing spontaneous withdrawal from oxycodone bury fewer marbles after longitudinal RBC1HI treatment (Sham-Oxy-Veh n = 6, Sham-Oxy-RBC1HI n = 7; unpaired t-test t = 3.663, df=11, p = 0.0037). Values are represented as mean ± SEM **p < 0.01, ****p < 0.0001.

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Pryce, K.D., Serafini, R.A., Ramakrishnan, A. et al. Oxycodone withdrawal induces HDAC1/HDAC2-dependent transcriptional maladaptations in the reward pathway in a mouse model of peripheral nerve injury. Nat Neurosci 26, 1229–1244 (2023). https://doi.org/10.1038/s41593-023-01350-3

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