Chemical multiplexing in the nervous system: molecular architecture, functional stratification, and pathophysiological plasticity of neuropeptide-classical neurotransmitter cotransmission.

Neurons frequently synthesize both neuropeptides and classical low-molecular-weight neurotransmitters, challenging the historical interpretation of one-neuron-one-transmitter signaling. Rather than representing biochemical redundancy, coexistence reflects a conserved organizational strategy that expands neural coding capacity through chemical multiplexing. Dual vesicular architecture-small clear vesicles for rapid synaptic transmission and large dense-core vesicles for activity-dependent peptide release-creates stimulus-intensity-dependent recruitment of distinct signaling layers. Classical transmitters primarily mediate millisecond-scale synaptic precision, whereas peptides engage slower G-protein-coupled receptor pathways that modulate excitability, plasticity, gene expression, and neuron-glia interactions. Across mammalian circuits, cotransmission regulates oscillatory coherence, learning and memory, motivational states, endocrine integration, sensory gain control, and autonomic balance. Peptidergic signaling is transcriptionally regulated and dynamically remodeled during development, stress, injury, and disease. Dysregulation contributes to chronic pain, addiction, stress-related disorders, epilepsy, cardiovascular dysfunction, and neurodegeneration. Therefore, neuropeptide-neurotransmitter coexistence constitutes a core computational principle of the nervous system, enabling temporal stratification and adaptive plasticity without expanding anatomical connectivity. Understanding chemical multiplexing is essential for linking molecular dynamics to circuit stability and vulnerability in health and disease.