Schizophrenia is a complex, multifactorial neuropsychiatric disorder in which many patients continue to experience disabling negative and cognitive symptoms despite treatment with dopamine-based antipsychotics. This therapeutic limitation has intensified the search for alternative neurobiological pathways that more directly regulate stress, affective processing, and salience. Increasing translational evidence indicates the dynorphin–kappa opioid receptor (DYN–KOR) pathway as a vital molecular regulator within cortico–striatal–limbic circuits that are impaired in schizophrenia. Dynorphins, derived from the prodynorphin precursor, serve as endogenous ligands for kappa opioid receptors (KORs) situated in the mesolimbic and prefrontal networks. The activation of this system affects multiple neurotransmitter pathways, including dopaminergic, glutamatergic, and GABAergic transmission. Kappa opioid receptor stimulation at the intracellular level activates stress-responsive pathways, including c-Jun N-terminal kinase signaling, resulting in changes to synaptic plasticity, motivation, and cognitive integration. These molecular effects parallel the behavioral domains most resistant to current pharmacotherapy. In humans, selective KOR agonists consistently induce perceptual abnormalities, dysphoria, and cognitive impairment, closely mirroring essential characteristics of psychosis. The effects are swiftly counteracted by opioid antagonists, validating a receptor-specific mechanism. Clinical biomarker studies indicate altered dynorphin levels in the cerebrospinal fluid of individuals with schizophrenia, with heightened concentrations associated with greater symptom severity and poor long-term outcomes. In accordance with these findings, animal models demonstrate that KOR activation leads to anhedonia, aversion, and sensory-gating deficits, while pharmaceutical KOR inhibition reinstates reward sensitivity and cognitive function. The combined genetic, behavioral, and clinical data support a revised neuropharmacological framework in which dysregulated DYN–KOR signaling contributes to the pathogenesis of schizophrenia. Focusing on this system may provide a promising therapeutic approach for symptom domains that current medications poorly address.

Dynorphin, Kappa opioid receptor, Schizophrenia, Neurotransmitter dysregulation, Translational neuropharmacology