The functional architecture of PACAP: A network-level framework of competing circuits for precision...

The neuropeptide PACAP presents a profound pharmacological paradox, acting as a potent neuroprotectant while often driving stress and nociception. To reconcile these opposing functions, this review proposes a network-level framework. While dual-process models are established in valence encoding, we apply this logic specifically to the PACAPergic system to resolve its functional pleiotropy. We argue that PACAP's functional pleiotropy is an emergent property of its role as a key modulator within functionally antagonistic macro-circuits. Specifically, we synthesize evidence showing that PACAP signaling modulates the gain of both a Pro-Aversive Network (centered on the extended amygdala) and a Pro-Adaptive Network (centered on the hippocampus and cortical structures). Mechanistically, we hypothesize that this gain control is achieved through differential receptor coupling, where specific splice variants and endosomal signaling dynamics bias threat circuits toward rapid excitability and resilience circuits toward sustained plasticity. We critically address contradictory data, such as mixed effects in pain modulation and hippocampal anxiety, positing that the final behavioral outcome is determined by the net balance of PACAPergic modulation on these competing macro-circuits. This architecture creates a translational challenge: systemic agonists risk amplifying maladaptive processes. To overcome this, we advocate for therapies designed to recalibrate network balance using isoform-selective ligands or allosteric modulation, rather than relying solely on systemic activation or blockade.