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bioRxiv · 10.64898/2026.10.07.755626

Differential utilization of PACAP and glutamate in parabrachial neurons shapes pain and stress

Singh, S.·Jiang, S. Z.·Rosado, W. J. F.·Brancaleone, W.·Rolon, D. C.·Tejeda, H.·Eiden, L. E.·Carrasquillo, Y.
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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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Singh, S., Jiang, S. Z., Rosado, W. J. F., Brancaleone, W., Rolon, D. C., Tejeda, H., Eiden, L. E., Carrasquillo, Y.. 2026-10-11. Differential utilization of PACAP and glutamate in parabrachial neurons shapes pain and stress. https://doi.org/10.64898/2026.10.07.755626

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