Corticosteroid sensitization drives opioid addiction

Hot Off the Press – April 5, 2022

Published in Molecular Psychiatry by Stephanie Carmack and Leandro Vendruscolo et, al. of the NIDA IRP Neurobiology of Addiction Section.

Summary

The sharp increase in opioid overdose-related deaths in the United States is a public health emergency. An urgent search to uncover the biological mechanisms of opioid use disorder (OUD) is underway with the goal of identifying potential therapeutic targets. In a new study published in Molecular Psychiatry, researchers from nine institutions, led by the Integrative Neuroscience Research Branch in the NIDA Intramural Research Program, investigated the role of brain stress systems in driving opioid addiction-like behavior.

Opioid withdrawal is a severely emotionally painful state (hyperkatifeia) that activates specific stress-engaged brain circuits. Intense stress leads to high levels of corticosteroids, such as glucocorticoids, circulating in the body. The researchers found evidence for glucocorticoid receptor-dependent changes in stress systems in opioid dependence across three species: humans, rats, and zebrafish. Blocking glucocorticoid receptors reduced opioid addiction-like behaviors in male and female rats and zebrafish. It also decreased a marker of brain stress system activation, excitability of corticotropin-releasing factor neurons, in the rat amygdala. The researchers additionally found evidence for adaptations in glucocorticoid receptor signaling in the amygdala of humans with OUD. The team concludes that this brain system may represent a target to treat the “stress side” of OUD. The graphic (Figure 6 in the published paper) illustrates how this glucocorticoid receptor signaling pathway may change in the central amygdala in opioid dependence.

Publication Information

Carmack, Stephanie A; Vendruscolo, Janaina C M; McGinn, M Adrienne; Miranda-Barrientos, Jorge; Repunte-Canonigo, Vez; Bosse, Gabriel D; Mercatelli, Daniele; Giorgi, Federico M; Fu, Yu; Hinrich, Anthony J; Jodelka, Francine M; Ling, Karen; Messing, Robert O; Peterson, Randall T; Rigo, Frank; Edwards, Scott; Sanna, Pietro P; Morales, Marisela; Hastings, Michelle L; Koob, George F; Vendruscolo, Leandro F

Corticosteroid sensitization drives opioid addiction Journal Article

In: Mol Psychiatry, 2022, ISSN: 1476-5578.

Abstract | Links

@article{pmid35296810,

title = {Corticosteroid sensitization drives opioid addiction},

author = {Stephanie A Carmack and Janaina C M Vendruscolo and M Adrienne McGinn and Jorge Miranda-Barrientos and Vez Repunte-Canonigo and Gabriel D Bosse and Daniele Mercatelli and Federico M Giorgi and Yu Fu and Anthony J Hinrich and Francine M Jodelka and Karen Ling and Robert O Messing and Randall T Peterson and Frank Rigo and Scott Edwards and Pietro P Sanna and Marisela Morales and Michelle L Hastings and George F Koob and Leandro F Vendruscolo},

url = {https://pubmed.ncbi.nlm.nih.gov/35296810/},

doi = {10.1038/s41380-022-01501-1},

issn = {1476-5578},

year  = {2022},

date = {2022-03-01},

urldate = {2022-03-01},

journal = {Mol Psychiatry},

abstract = {The global crisis of opioid overdose fatalities has led to an urgent search to discover the neurobiological mechanisms of opioid use disorder (OUD). A driving force for OUD is the dysphoric and emotionally painful state (hyperkatifeia) that is produced during acute and protracted opioid withdrawal. Here, we explored a mechanistic role for extrahypothalamic stress systems in driving opioid addiction. We found that glucocorticoid receptor (GR) antagonism with mifepristone reduced opioid addiction-like behaviors in rats and zebrafish of both sexes and decreased the firing of corticotropin-releasing factor neurons in the rat amygdala (i.e., a marker of brain stress system activation). In support of the hypothesized role of glucocorticoid transcriptional regulation of extrahypothalamic GRs in addiction-like behavior, an intra-amygdala infusion of an antisense oligonucleotide that blocked GR transcriptional activity reduced addiction-like behaviors. Finally, we identified transcriptional adaptations of GR signaling in the amygdala of humans with OUD. Thus, GRs, their coregulators, and downstream systems may represent viable therapeutic targets to treat the "stress side" of OUD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}