30 years of dynorphins--new insights on their functions in neuropsychiatric diseases

Abstract

Since the first description of their opioid properties three decades ago, dynorphins have increasingly been thought to play a regulatory role in numerous functional pathways of the brain. Dynorphins are members of the opioid peptide family and preferentially bind to kappa opioid receptors. In line with their localization in the hippocampus, amygdala, hypothalamus, striatum and spinal cord, their functions are related to learning and memory, emotional control, stress response and pain. Pathophysiological mechanisms that may involve dynorphins/kappa opioid receptors include epilepsy, addiction, depression and schizophrenia. Most of these functions were proposed in the 1980s and 1990s following histochemical, pharmacological and electrophysiological experiments using kappa receptor-specific or general opioid receptor agonists and antagonists in animal models. However, at that time, we had little information on the functional relevance of endogenous dynorphins. This was mainly due to the complexity of the opioid system. Besides actions of peptides from all three classical opioid precursors (proenkephalin, prodynorphin, proopiomelanocortin) on the three classical opioid receptors (delta, mu and kappa), dynorphins were also shown to exert non-opioid effects mainly through direct effects on NMDA receptors. Moreover, discrepancies between the distribution of opioid receptor binding sites and dynorphin immunoreactivity contributed to the difficulties in interpretation. In recent years, the generation of prodynorphin- and opioid receptor-deficient mice has provided the tools to investigate open questions on network effects of endogenous dynorphins. This article examines the physiological, pathophysiological and pharmacological implications of dynorphins in the light of new insights in part obtained from genetically modified animals.

Figure 1. Biosynthesis of pDyn derived peptides

The entire coding sequence of pDYN is contained in exons 3 and 4 (dark grey shading) of the pDYN gene. Several differentially spliced transcripts are derived from this single gene, however only the two full-length mRNAs FL1 and FL2 are found in humans and rodents. These two splice variants differ only in the 5′-non-coding region with FL2 being transcribed from an extended exon 2 (light grey). An identical 254-amino acid preprodynorphin is translated from both mRNAs. The first 20 amino acids represent the signal peptide, responsible for targeting the protein towards the endoplasmatic reticulum. This peptide is immediately cleaved by the signal peptidase, resulting in pDYN. Further processing is differentially regulated in distinct brain regions, resulting in pDYN as well as mature peptides in axon terminals. Maturation is dependent on prohormone convertases PC1 and PC2. Processing of the mature peptides at the paired arginine residues yields Leu-enkephalin from β-neoendorphin, DYN A and DYN B.

Figure 2. Potential sites of Dyn/KOP interactions in the hippocampus

Dyn immunoreactivity is observed mainly in axons of granule cells (gc) termed mossy fibers (mf). Dyn released from these axons may target presynaptic KOP on mossy fibers, either as autoreceptor or on axon collaterals. Postsynaptic KOP on hilar somatostatin - neuropeptide Y - GABA interneurons, or on dendrites of CA3 pyramidal neurons represent another pool of targets. Also the dendrites of granule cells contain large dense core vesicles loaded with Dyn. Dendritic release in the molecular layer (ml) may target presynaptic KOP on perforanth path (pp) terminals, or on postsynaptic KOP located on granule cell dendrites in the inner and outer molecular layer. In humans, also perforanth path fibers were shown to contain Dyn. These fibers innervate the molecular layer of the dentate gyrus (DG), but also dendrites of CA1 pyramidal neurons. In the inner molecular layer of the dentate gyrus presynaptic KOP on terminals of supramammillary projections were shown in guinea pigs. a...alveus; so...stratum oriens; sr...stratum radiatum; sml...stratum lacunosum moleculare.

Figure 3. Potential sites of Dyn/KOP interactions in emotional control

pDyn mRNA and Dyn peptides are widely distributed in brain nuclei involved in emotional control. For KOP, there is a certain mismatch of mRNA and binding sites, suggesting axonal transport of the receptor mainly in serotonergic and mesolimbic dopaminergic projections. Presynaptic KOP on these axons was also suggested from pharmacologicla studies. Most other forebrain nuclei involved in emotional control display both, Dyn and KOP labeling, supporting a strong influence of Dyn on these circuits. Not all projections and tracts are clearly identified, but presently the suppression of dopamine release by KOP activation from VTA - NAc projections appears highly important in depression and addiction. Dyn controls dopamine release from these fibers potentially at least in part through presynaptic KOP autoreceptors. Serotonin release from fibers originating in the dorsal raphe is stimulated by MOP and decreased by KOP, which was made responsible for effects on anxiety like behavior. The noradrenergic innervation of the forebrain is also controlled through Dyn, mainly directly in the locus ceruleus. This includes postsynaptic KOP on noradrenergic neurons, but also presynaptic KOP on excitatory fiber terminals in the locus ceruleus. KOP acting as autoreceptors were described on granule cell dendrites in the molecular layer of the hippocampus. This position allows them to regulating the excitability of the main hippocampal input structure, the granule cell layer. Also on dendrites of arginine-vasopressin expressing neurons in the superoptic nucleus autoreceptors were observed, most probably being responsible for the opioid induced reduction of arginine-vasopressin and oxytocin release. Somatodendritic autoreceptors are targeted by somatodendritical released Dyn. Acb...nucleus accumbens; Amy...amygdaloid complex; Arc...arcuate hypothalamic nucleus; Ce...central amygdaloid nucleus; CPu...caudate putamen (striatum); DR...dorsal raphe nucleus; Hipp...hippocampus; LRt...lateral reticular nucleus; PFC...prefrontal cortex; Pit...pituitary gland; PVN...paraventricular hypothalamic nucleus; Sept...septum; SO...superoptic nucleus; Sol...nucleus of the solitary tractus; VTA...ventral tegmental area;