Dynorphin, Analogs and Sequences

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What is the Dynorphin?

Dynorphins are a category of endogenous opioid peptides that predominantly interact with the kappa-opioid receptor (KOR), a member of the G-protein-coupled receptor (GPCR) family. They also engage with other opioid receptors, including the mu-opioid receptor (MOR) and delta-opioid receptor (DOR), though with diminished affinity. The mechanism of action of dynorphins is complex, encompassing receptor binding, activation of subsequent signaling pathways, and modulation of neuronal activity.

Function of dynorphin. (Agostinho A S., et al., 2019)

Dynorphin structure

Dynorphin is a member of the peptide family that results from the posttranslational modification of prodynorphin. They can be found in peripheral tissues like the adrenal gland, gastrointestinal tract, and heart, as well as in the central nervous system. The large precursor prodynorphin undergoes posttranslational processing to produce various bioactive peptides known as dysorphins. These include α-neoendorphin (α-NE), big dynorphin (Dyn A 1-32), leumorphin (Dyn B 1-29), dynorphin A (Dyn A 1-17), dynorphin B (Dyn B 1-13), leucine-enkephalin-arginine (Leu-enkephalin-Arg), and possibly leucine-enkephalin (Leu-enkephalin).

A very powerful opioid peptide isolated from pituitary glands was described and partially sequenced in 1979 by Avram Goldstein et al. With the N-terminus containing the amino acid sequence for Leu-enkephalin, this tridecapeptide was almost 700 times more effective than Leu-enkephalin in the guinea pig ileum longitudinal muscle preparation. The Greek prefix dyn, meaning "strength" or "power," is the origin of its name, dynorphin (1–13). The full sequence of the endogenous heptadecapeptide Dyn A(l-17) was later disclosed by the same lab. Not long after that, several research facilities detailed the location and order of the other dynorphins.

The structure of Dynorphin (Dyn) A and B. (Spampinato S., et al., 2013)

Primary sequence of big dynorphin, dynorphin A and dynorphin B. (Hauser K F., et al., 2005)

Dynorphin mechanism of action

Dynorphins binds to κ-opioid receptors and act as inhibitory neurotransmitters and induce pain desensitization. Dynorphin's interaction with NMDA receptors increases intracellular calcium, resulting in neurotoxicity through intercellular (NOS → NO) or intracellular [protein kinase C (PKC)] signaling, alongside heightened transmitter release. Conversely, its effect on opioid receptors is likely neuroprotective through Gi-coupled signaling. Dynorphin A (1–13) is a breakdown product of dynorphin A which is synthesized as preprodynorphin. Apart from pain relieving roles, high concentration of dynorphins can induce hyperalgesia and allodynia or even the production of neurodegeneration metabolites. The interaction of dynorphin-13 with κ-opioid and NMDA receptors. Dynorphin A (1–13) interacts with the κ-opioid receptor and NMDA-glutamatergic systems. ACE2 destroys dynorphin A 1–13, resulting in the formation of dynorphin A 1–12. SARS-CoV-2 diminishes ACE2 expression, leading to the detrimental consequences of dynorphin A 1–13 accumulation, which results in neuronal death through NMDA receptor activation.

The mechanism of Dynorphin. (Laughlin T M., et al., 2001)

The binding of dynorphin to κ-opioid and NMDA receptors. (Mehrabadi M E., et al., 2021)

Dynorphin function

Much like other neuropeptides, dynorphin stimulates KORs upon release from big packed core vesicles in reaction to prolonged neuronal activity. KORs normally reduce synaptic transmission by activating voltage-gated K⁺ channels, inhibiting voltage-gated Ca²⁺ channels, and coupling to inhibitory Gi/o-proteins. Decreased synaptic transmission may also result from activation of presynaptic KORs, which directly impede vesicle fusion. Aside from the immediate impact on ion channel conductance, KORs trigger signal transduction cascades that involve mitogen-activated protein kinases (MAPKs). These cascades subsequently activate transcription factors, leading to changes in gene expression. There is mounting evidence that neurons regulate their own activity by activity-dependent dynorphin release, which may be particularly potent from dendritic locations. The secretion of dendritic dynorphins in the hypothalamus and hippocampus effectively controls excitatory inputs by activating presynaptic KORs retrogradely. It is possible that this inhibitory mechanism extends to dendritic dynorphin-expressing neuronal groups in the amygdala and striatum, which are involved in mood and motivation modulation. The release of dendritic neuropeptides has the potential to act as an additional inhibition mechanism that may be activated quickly and widely in reaction to excessive neuronal activity, without interfering with or straining the current feedforward and feedback inhibitory circuits. Since preexisting inhibitory circuits play an essential role in neurons' computational processes, this supplementary reduction mechanism may aid in maintaining information processing under circumstances of high activity in neurons, like stress, which causes the limbic brain to release dynorphin.

The function of KORs in mood regulation remains incompletely elucidated; nonetheless, dynorphin and KORs are present in limbic brain regions associated with the pathophysiology of depression and anxiety disorders. These regions encompass the mesocorticolimbic dopamine system, which includes the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC); the serotonergic and noradrenergic systems, which consist of principal cell groups in the dorsal raphe nucleus and locus coeruleus, respectively; the extended amygdala, comprising the central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (BNST), and NAc shell; as well as the basolateral amygdala, hippocampus (HIP), and hypothalamus in both humans and rodents. This review primarily examines the connections between KORs and dopaminergic systems, as extensive knowledge exists regarding the impact of dopamine function alterations on motivation, which is consistently dysregulated in depressive illnesses. It is evident that KORs also participate in the regulation of serotonergic and noradrenergic systems, which are the principal targets of conventional antidepressant medications. A comprehensive characterization of the interconnections between serotonin and norepinephrine is critical for a complete knowledge of the neurobiology of mood, given their significant roles in stress and behavior. Ultimately, dynorphin expression coincides with that of other neuropeptide systems implicated in stress and motivation, including as CRF, neuropeptide Y, and vasopressin. The KOR system is optimally situated to exert widespread influence on behavior, potentially functioning as a regulatory mechanism to mitigate increases in neuronal activity triggered by stress.

The activation of KOR signaling in the limbic system mediates the wide range of physiological and behavioral changes brought on by acute stress. Release of the feel-good chemical dopamine can happen as an outcome of increases in neuronal activity brought on by stress, or it can be a cause in and of itself. There is some evidence that the activation of KOR mediated by dynorphin contributes to the immediate effects of stress. In a perfect world, KOR activation would mostly lead to a reduction in neuronal activity among KOR-expressing cell populations. Pain encompasses both sensory and negative affective elements, which are governed by interconnected but distinct neural circuits. The lack of either component severely hinders protective reactions to harmful stimuli, as shown by negative consequences in congenital pain syndromes characterized by insensitivity or apathy to such stimuli. KOR signaling influences both sensory and emotional dimensions of pain, making it a highly effective integrator of protective responses. The activation of KORs induces analgesia by suppressing synaptic communication within brain pain circuits. Kappa opioid receptors (KORs) and dynorphin are present at multiple levels of the pain circuitry, including the dorsal root ganglia, dorsal horn of the spinal cord, rostral ventromedial medulla, periaqueductal gray, sensory thalamus, and limbic areas. The precise subcellular localization of KORs within these circuits remains unclear; however, pharmacological investigations involving wild-type, KOR^−/−, and PDyn^−/− mice indicate that KORs play significant roles in transmitting visceral, chemical, inflammatory, and thermal pain, whereas MORs and DORs seem to primarily transmit thermal and mechanical pain. Dynorphin has been associated with neuropathic pain through its effects on Kappa Opioid Receptors (KORs) and non-opioid receptors in the spinal cord.

The manifestation of stress-sensitive behaviors relies on stress-induced alterations in brain function that become apparent after later stress exposure. Multiple lines of evidence indicate that CREB-mediated elevations in dynorphin contribute to the manifestation of stress-sensitized behavior. Specifically, enhancing CREB activity in the NAc (via viral-mediated gene transfer) augments dynorphin gene expression and enhances immobility during the second swim session, a pro-depressive-like action that is inhibited by KOR antagonists. Conversely, diminishing CREB activity (via viral-mediated introduction of a dominant negative variant of CREB) leads to a reduction in dynorphin mRNA expression and a decrease in immobility, exhibiting an antidepressant-like effect. Swimming stress elevates pCREB levels in the NAc and enhances dynorphin in both the NAc and HIP, indicating that this biochemical cascade contributes to stress-induced behavioral adaptations under physiological conditions. Collectively, these findings indicate that heightened KOR signaling during the second swim session facilitates immobility. Notably, sub-chronic injection of the antidepressant desipramine, initiated one hour post-exposure to forced swimming, reduces immobility behavior in rats upon retesting 24 hours later and inhibits the elevation of PDyn mRNA in the NAc following swim stress. This suggests that medications exhibiting antidepressant-like properties may possess the capacity to reduce dynorphin signaling in the NAc. These findings may also offer broader insight into the mechanisms via which the FST swiftly identifies drugs with antidepressant properties in humans: Administering antidepressants shortly after stress exposure may inhibit the onset of neuroadaptations, such as elevated dynorphin expression, that contribute to the emergence and manifestation of depressive-like behavior.

Stress activates the release of hormones and neuropeptides, including dynorphin. (Knoll A T., et al., 2010)

Dynorphin peptide

Pro-dynorphin, also known as pro-enkephalin B, can be metabolized to yield dynorphin A, dynorphin B, α-neoendorphin, and β-neoendorphin. Pro-dynorphin is present in various regions of the central nervous system, including the hypothalamus, hippocampus, brainstem, amygdala, and gastrointestinal tract. The neurons responsible for dynorphin production in the hypothalamus are mostly situated in the supraoptic nucleus and the paraventricular nucleus. Dynorphins exhibit the highest affinity for the κ-opioid receptor. Dynorphins are less understood compared to other opioid groups, while their physiological effects vary significantly based on their manufacturing site. These effects encompass modulating the electrical activity of magnocellular neurons that synthesize AVP and the negative feedback control of oxytocin release. Dynorphins constitute a category of opioid peptides derived from the precursor protein prodynorphin. During the digestion of prodynorphin by proprotein convertase 2, many active peptides are liberated: dynorphin A, dynorphin B, and α/β-neo-endorphin. The cDNA of the precursor protein dynorphin, known as prodynorphin (gene name: PDYN), is also extracted.

Dynorphin A

Dynorphin A [dynorphin A (1-17)], a significant posttranslational product of the preprodynorphin gene (1–4), exhibits high affinity for kappa opioid receptors (KOR) and serves as an endogenous ligand that preferentially interacts with this receptor type. The amino acid sequence of dynorphin A (YGGFLRRIRPKLKWDNQ) is highly conserved and same among humans, rats, mice, bovines, pig species, and amphibians. The opioid and non-opioid glutamatergic receptors are intrinsically active with dynorphin A. Opioid receptors are activated by N-terminal peptide derivatives, while glutamate receptors can be activated by C-terminal fragments. Dynorphin generally activates kappa-opioid receptors (KOR) at physiological doses, allowing it to operate normally. Depending on the type of neural cell impacted, the timing of the insult, and the nature of the activation, opioid receptor activation can have positive or negative effects in isolated neurons. Alternatively, dynorphin A has excitotoxic effects on neurons and oligodendroglia, and it may destabilize astroglia, when it operates at supraphysiological levels via glutamate receptors.

The neuroprotective and deleterious affects of dynorphin A (1–17). (Hauser K F., et al., 2005)

Dynorphin B

The recent discovery that the byproduct of the prodynorphin gene, known as dysorphin B, primes cardiogenesis in P19 embryonal pluripotent cells suggests that endorphinergic systems might play a role in the development and maturation of myocardial cells. Dynorphin B also increased the rate of prodynorphin gene transcription when exposed to the nucleus. By incubating isolated nuclei with selective opioid receptor antagonists, these responses were inhibited in a stereospecific manner. Phosphorylation of the acrylodan-labeled MARCKS peptide, a substrate for high-affinity fluorescent protein kinase C, was seen in nuclei separated from undifferentiated cells. Opioid receptor antagonists reduced the dramatic rise in nucleus PKC activity that was induced by dynorphin B exposure of isolated nuclei. Dynorphin B's capacity to stimulate the transcription of cardiogenic genes was eliminated by nuclear treatment with PKC inhibitors.

References

1. Agostinho A S., et al., Dynorphin‐based "release on demand" gene therapy for drug‐resistant temporal lobe epilepsy, EMBO molecular medicine, 2019, 11(10): e9963.
2. Knoll A T., et al., Dynorphin, stress, and depression, Brain research, 2010, 1314: 56-73.
3. Spampinato S., et al., Prodynorphin-derived peptides[M]//Handbok of Biologically Active Peptides. Academic Press, 2013: 1596-1601.
4. Hauser K F., et al., Pathobiology of dynorphins in trauma and disease, Frontiers in bioscience: a journal and virtual library, 2005, 10: 216.
5. Laughlin T M., et al., Mechanisms of induction of persistent nociception by dynorphin, Journal of Pharmacology and Experimental Therapeutics, 2001, 299(1): 6-11.
6. Mehrabadi M E., et al., Induced dysregulation of ACE2 by SARS-CoV-2 plays a key role in COVID-19 severity, Biomedicine & Pharmacotherapy, 2021, 137: 111363.