Parabrachial-amygdala circuit cooperates with a posterior striatal area to drive opioid withdrawal aversion

Abstract

Opioid addiction treatment is often hampered by the severe dysphoria of opioid withdrawal, but withdrawal treatments are limited by incomplete understanding of brain mechanisms involved. One area frequently implicated in withdrawal symptoms is the central amygdala, whose capsular portion (CeC) is particularly strongly activated during withdrawal. Additionally, a ventral posterior striatal region that resides near CeC, the interstitial nucleus of the posterior limb of the anterior commissure (IPACc), is also activated as strikingly as CeC. However, it is still unknown how these regions are activated, nor whether their activation explains the high intensity of withdrawal dysphoria. Using RNAscope, we found that c-fos expression is induced in the parabrachial nucleus (PB), a key glutamatergic afferent of CeC, after precipitated morphine withdrawal. Chemogenetic inhibition of PB glutamatergic neurons (VG2PB) nearly eliminated withdrawal-induced CeC c-Fos, without affecting IPACc c-Fos, indicating these two nuclei are activated by distinct sources. Furthermore, VG2PB inhibition markedly reduced somatic (jumping) and modestly reduced affective (place avoidance) withdrawal behavior. On the other hand, inhibition of CeC-projecting PB neuronal subtypes expressing calcitonin gene-related peptide (CGRP) or mu opioid receptor (MOR) reduced place avoidance without affecting jumping, indicating their specific role in withdrawal aversion. Strikingly, simultaneous inhibition of VG2PB and posterior striatal region containing IPACc robustly reduced withdrawal-induced place avoidance much more than the modest effects of either inhibition alone, suggesting their cooperative action in driving aversion. Our data suggests that PB-CeC circuit and posterior striatal area constitute a cooperative system driving opioid withdrawal aversion.

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BibTeX RIS

BibTeX

@misc{lee2026parabrachialamygdala,
  title = {{Parabrachial-amygdala circuit cooperates with a posterior striatal area to drive opioid withdrawal aversion}},
  author = {S.-C. Lee and K. A. Shimoda and J. D. Ross and J. M. Coudriet and T. Jhou and S. Ikemoto},
  howpublished = {bioRxiv},
  year = {2026},
  month = aug,
  doi = {10.64898/2026.08.27.747629},
  url = {https://www.biorxiv.org/content/10.64898/2026.08.27.747629v1},
  note = {CC0},
}

RIS

TY  - UNPB
TI  - Parabrachial-amygdala circuit cooperates with a posterior striatal area to drive opioid withdrawal aversion
AU  - S.-C. Lee
AU  - K. A. Shimoda
AU  - J. D. Ross
AU  - J. M. Coudriet
AU  - T. Jhou
AU  - S. Ikemoto
PY  - 2026
DA  - 2026/08/27
PB  - bioRxiv
DO  - 10.64898/2026.08.27.747629
UR  - https://www.biorxiv.org/content/10.64898/2026.08.27.747629v1
AB  - Opioid addiction treatment is often hampered by the severe dysphoria of opioid withdrawal, but withdrawal treatments are limited by incomplete understanding of brain mechanisms involved. One area frequently implicated in withdrawal symptoms is the central amygdala, whose capsular portion (CeC) is particularly strongly activated during withdrawal. Additionally, a ventral posterior striatal region that resides near CeC, the interstitial nucleus of the posterior limb of the anterior commissure (IPACc), is also activated as strikingly as CeC. However, it is still unknown how these regions are activated, nor whether their activation explains the high intensity of withdrawal dysphoria. Using RNAscope, we found that c-fos expression is induced in the parabrachial nucleus (PB), a key glutamatergic afferent of CeC, after precipitated morphine withdrawal. Chemogenetic inhibition of PB glutamatergic neurons (VG2PB) nearly eliminated withdrawal-induced CeC c-Fos, without affecting IPACc c-Fos, indicating these two nuclei are activated by distinct sources. Furthermore, VG2PB inhibition markedly reduced somatic (jumping) and modestly reduced affective (place avoidance) withdrawal behavior. On the other hand, inhibition of CeC-projecting PB neuronal subtypes expressing calcitonin gene-related peptide (CGRP) or mu opioid receptor (MOR) reduced place avoidance without affecting jumping, indicating their specific role in withdrawal aversion. Strikingly, simultaneous inhibition of VG2PB and posterior striatal region containing IPACc robustly reduced withdrawal-induced place avoidance much more than the modest effects of either inhibition alone, suggesting their cooperative action in driving aversion. Our data suggests that PB-CeC circuit and posterior striatal area constitute a cooperative system driving opioid withdrawal aversion.
ER  -

Abstract

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