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

The external parabrachial nucleus (elPBN) plays a role in various behaviors, including pain and stress. Glutamatergic and neuropeptidergic signaling occur in this region, with pituitary adenylate cyclase-activating polypeptide (PACAP) expressed in a portion of glutamatergic neurons. Researchers have found that eliminating PACAP in elPBN neurons reduces behavioral responses to stress, but the effect on pain sensitization and the role of glutamatergic neurotransmission in pain and stress-related responses are still unclear.

This study reveals that removing PACAP significantly lessens hypersensitivity caused by nerve injuries across heat, pressure, cold, and tactile sensations, without affecting baseline pain perception. Additionally, it decreases inflammation-induced spontaneous pain-related behavior. However, when PACAP was selectively removed within elPBN neurons, inflammation-induced pain-related behavior remained unaffected.

Ex vivo optogenetic-assisted circuit mapping showed that activating PACAP-expressing elPBN terminals stimulated glutamatergic transmission onto central amygdala (CeA) neurons with phosphoinositide 3-kinase delta (PKC) delta. Deleting VGluT2 in elPBN neurons reduced nerve injury-induced hypersensitivity but also decreased inflammation-induced pain-related behavior, unlike PACAP deletion.

Interestingly, stress-induced hypophagia remained unaffected by VGluT2 deletion. These findings suggest that PACAP and glutamatergic neurotransmission have distinct roles within the elPBN in pain- and stress-related behaviors.