The dynorphin/κ-opioid receptor system and its role in psychiatric disorders

Abstract

The dynorphin/κ-opioid receptor system has been implicated in the pathogenesis and pathophysiology of several psychiatric disorders. In the present review, we present evidence indicating a key role for this system in modulating neurotransmission in brain circuits that subserve mood, motivation, and cognitive function. We overview the pharmacology, signaling, post-translational, post-transcriptional, transcriptional, epigenetic and cis regulation of the dynorphin/κ-opioid receptor system, and critically review functional neuroanatomical, neurochemical, and pharmacological evidence, suggesting that alterations in this system may contribute to affective disorders, drug addiction, and schizophrenia. We also overview the dynorphin/κ-opioid receptor system in the genetics of psychiatric disorders and discuss implications of the reviewed material for therapeutics development.

Fig. 1

To scale schematics of PDYN (a) and OPRK1 (b). Shown are functional sequence variants associated with psychiatric disorders (e.g., rs35286281) and transcriptional control proteins implicated in the regulation of these genes (positioned relative to the transcription start sites). Transcriptional control proteins for which there is in vivo evidence of binding are depicted above the sequence (e.g., REST), and those for which only in vitro evidence is available below the sequence (e.g., AP-1). ║ genomic regions omitted for clarity, boxes exons, white boxes coding regions, black arrows transcription start sites, green arrows alternative transcription start sites

Fig. 2

The figure depicts a simplified scheme of neuronal circuits implicated in psychiatric disorders that are modulated by DYN/KOR pathways. DYN-positive neurons are located in the hypothalamus, central nucleus of the amygdala, cortical, and striatal regions and innervate neural substrates rich in KORs. DYN-positive neurons are innervated by glutamatergic and monoaminergic fibers containing presynaptic KORs, providing a physiological substrate for DYN/KOR to modulate presynaptic monoaminergic neurotransmission. The inset provides a key of neuronal/fiber type and simplified scheme of localization of KORs and DYN-positive neurons