Evolution of neuropeptides: from diffusing molecules to modulators of synaptic transmission

Neuropeptides are evolutionarily ancient signaling molecules that predate neurons and the central nervous system, yet they now function as powerful regulators of physiology and complex behavior. This review proposes that their success derives from a spectrum of “modes of action,” ranging from free diffusion and volume transmission in early metazoans to more spatially restricted, circuit-specific modulation in bilaterians and vertebrates. In cnidarians, decentralized nerve nets still use peptidergic volume transmission to coordinate motor programs and behavioral plasticity, consistent with the idea that diffuse peptide signaling preceded synaptic wiring. As nervous systems centralized (e.g., tunicates, cephalochordates), neuropeptide families expanded and signaling became compartmentalized. In vertebrates, the blood-brain barrier and hypothalamo-pituitary axis enabled dual roles: endocrine hormones in the periphery and neuromodulators in the brain. The review argues that diffusion through the cerebrospinal fluid and focal axonal/dendritic release are complementary, with functional specificity determined by release site and receptor distribution. Neuropeptides also co-act with monoamines and fast amino-acid transmitters via co-release and pre-/post-synaptic modulation, providing layered control across timescales. Emerging biosensors and modern circuit tools are positioned to resolve peptide spatiotemporal dynamics and accelerate translational opportunities despite delivery constraints. • Neuropeptides predate neurons and enabled early intercellular signaling • Evolution shifted signaling from diffusion to circuit-specific modulation • Local and volume transmission coexist as complementary modes • Functional specificity depends on release site, receptor distribution, and types of receptive cells • Co-release with neurotransmitters enables multi-scale circuit regulation