Differential utilization of PACAP and glutamate in parabrachial neurons shapes pain and stress
- 1National Institutes of Health
Abstract
The external parabrachial nucleus (elPBN) contributes to diverse behaviors, including pain and stress. Neurons in this region use glutamatergic and neuropeptidergic signaling, with pituitary adenylate cyclase-activating polypeptide (PACAP) expressed in a subset of glutamatergic neurons. Deletion of PACAP in elPBN neurons attenuates behavioral responses to stress, but the contribution of PACAP to pain sensitization and of glutamatergic neurotransmission to pain- and stress-related responses remain poorly understood. Here, we show that constitutive loss of PACAP markedly attenuated nerve injury-induced hypersensitivity across heat, pressure, cold and tactile modalities without altering baseline nociception, while also reducing inflammation-induced spontaneous pain-related behavior. Notably, selective deletion of PACAP within elPBN neurons phenocopied the suppression of injury-induced hypersensitivity, but left inflammation- induced pain-related behavior unaffected. Ex vivo optogenetic-assisted circuit mapping showed that activation of PACAP-expressing elPBN terminals elicited glutamatergic transmission onto central amygdala (CeA) PKC{delta}-expressing neurons. Selective deletion of VGluT2 in elPBN neurons reduced nerve injury-induced hypersensitivity but, unlike PACAP deletion, also reduced inflammation-induced pain-related behavior, while leaving stress-induced hypophagia intact. Together, these findings reveal differential requirements for PACAP and glutamatergic neurotransmission within the elPBN across pain- and stress-related behaviors.
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BibTeX
@misc{singh2026differential,
title = {{Differential utilization of PACAP and glutamate in parabrachial neurons shapes pain and stress}},
author = {S. Singh and S. Z. Jiang and W. J. F. Rosado and W. Brancaleone and D. C. Rolon and H. Tejeda and L. E. Eiden and Y. Carrasquillo},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.07.755626},
url = {https://www.biorxiv.org/content/10.64898/2026.10.07.755626v1},
note = {CC0},
}
RIS
TY - UNPB
TI - Differential utilization of PACAP and glutamate in parabrachial neurons shapes pain and stress
AU - S. Singh
AU - S. Z. Jiang
AU - W. J. F. Rosado
AU - W. Brancaleone
AU - D. C. Rolon
AU - H. Tejeda
AU - L. E. Eiden
AU - Y. Carrasquillo
PY - 2026
DA - 2026/10/07
PB - bioRxiv
DO - 10.64898/2026.10.07.755626
UR - https://www.biorxiv.org/content/10.64898/2026.10.07.755626v1
AB - The external parabrachial nucleus (elPBN) contributes to diverse behaviors, including pain and stress. Neurons in this region use glutamatergic and neuropeptidergic signaling, with pituitary adenylate cyclase-activating polypeptide (PACAP) expressed in a subset of glutamatergic neurons. Deletion of PACAP in elPBN neurons attenuates behavioral responses to stress, but the contribution of PACAP to pain sensitization and of glutamatergic neurotransmission to pain- and stress-related responses remain poorly understood. Here, we show that constitutive loss of PACAP markedly attenuated nerve injury-induced hypersensitivity across heat, pressure, cold and tactile modalities without altering baseline nociception, while also reducing inflammation-induced spontaneous pain-related behavior. Notably, selective deletion of PACAP within elPBN neurons phenocopied the suppression of injury-induced hypersensitivity, but left inflammation- induced pain-related behavior unaffected. Ex vivo optogenetic-assisted circuit mapping showed that activation of PACAP-expressing elPBN terminals elicited glutamatergic transmission onto central amygdala (CeA) PKC{delta}-expressing neurons. Selective deletion of VGluT2 in elPBN neurons reduced nerve injury-induced hypersensitivity but, unlike PACAP deletion, also reduced inflammation-induced pain-related behavior, while leaving stress-induced hypophagia intact. Together, these findings reveal differential requirements for PACAP and glutamatergic neurotransmission within the elPBN across pain- and stress-related behaviors.
ER -