Dynorphin

2022-04-08: reference:

Dynorphin #

• Prodynorphin cleavage generates dynorphin A/B and α/β-neo-dynorphin. (neo wtf?)

  • Prodynorphin is colocalized with proprotein convertase 2 (PC2), which plays a role in dynorphins’s synthesis, probably ProDyn’s cleavage.
  • Nonopiate effects of dynorphin and des-Tyr-dynorphin
    • The first AA of dynorphin A = tyrosine, and that’s essential for its κ-Opioid Receptor effects. The second and third are glycine. #Ankified
    • des-Tyr-dynorphin is less potent at inhibiting NMDA currents #Ankified

• Binds to κ-Opioid Receptors (with slight affinity for μ-Opioid Receptor, δ-Opioid Receptor), agonism inhibits dopamine release.

  • Blocks NMDAR directly: The opioid peptide dynorphin directly blocks NMDA receptor channels in the rat
    • The inhibitory action of dynorphin cannot be blocked by high concentration of naloxone, nor by Norbinalt.
  • Dynorphin displaces binding at the glycine site of the NMDA receptor in the rat striatum but it actually potentiates it, at least under low glycine conditions:
    • Potentiation of NMDA Receptor-Mediated Responses by Dynorphin at Low Extracellular Glycine Concentrations. I’m not sure what the actual ’link’ is with Glycine concentrations as it relates to the state of the organism, but I guess maybe you could say dynorphin is therefore keeping NMDA currents ‘in check’; in the presence of high co-agonist it inhibits. And this isn’t out of left field or anything; it can be coreleased with glutamate at glutamate synapses.
      • This is a KOR-independent mechanism, hence nor-BNI not helping. #Ankified
  • These κ-Opioid Receptors are found on the terminals of dopaminergic projections.
    • Inhibits NMDA-induced 3H-dopamine release in the striatum (just like pregnenolone).

• Its dysphoric effects are mediated by stimulating CRH release.

• Dense-core vesicles, such as those holding peptides, are much larger, and require much longer/intense stimuli for exocytosis.

  • Dynorphin plays a role in addiction. One exposure to something like Cocaine induces no increase, but chronic exposure does lead to an increase in concentration in the Striatum and Substantia Nigra. This is mediated by CREB (given that cocaine increases cAMP/PKA and all that.)
    • Thus with CREB it makes sense that it’s often observed together with increased amounts of ΔFosB, HOWEVER FosB downregulates the κ-opioid component in one way or another. Gotta look into that one.

• Stress Produces Aversion and Potentiates Cocaine Reward by Releasing Endogenous Dynorphins in the Ventral Striatum to Locally Stimulate Serotonin Reuptake

  • → p38α MAPK → SERT translocation to the synaptic terminals of serotonergic neurons.
  • Although the serotonergic neurons in the dorsal raphe project throughout the forebrain, a significant stress-induced increase in cell-surface SERT expression was only evident in the ventral striatum.
  • Indeed, proynorphin neurons are distributed in areas associated with stress, but in terms of regions a lot of place including the Hypothalamus, Hippocampus, Brain Stem, Amygdala, GI tract, Stiatum.
    • Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit

• Locomotor activities were normal in Pdyn-deficient mice and THC-evoked conditioned place aversion was abolished in high-dosage paradigms. These data suggest that the κ-opioid signaling system mediates the aversive site of hedonic homeostasis in motivational circuits.

• Dynorphins regulate fear memory: from mice to men.

  • Mice lacking dynorphin showed an enhanced cue-dependent fear conditioning, as well as delayed extinction in contextual conditioning/extinction paradigms

• Microinjection of dynorphin into the hippocampus impairs spatial learning in rats

• Arbiters of endogenous opioid analgesia: role of CNS estrogenic and glutamatergic systems

  • The disconnection of suppressive membrane ERα-mGluR1 signaling, the transition from mERα to glutamate (Glut) activation of mGluR1, which now signals in partnership with mGluR2/3, and augmented spinal Dyn/KOR signaling, which signals in collaboration with MOR in an oligomer of mGluR1-mGluR2/3-KOR-MOR that is different from that of diestrus, triggers the appearance of spinal EM2 analgesia. Inhibition of Glut release and thus a decrease in mGluR1/mGluR2/3 signaling activity eliminates the expression of endogenous spinal opioid analgesia,