41. Natalka Parzei

Glutamatergic pre-Bötzinger complex neurons as potential targets to alleviate opioid-induced respiratory depression.

4 Comments

  • Richard Horner says:

    Nice poster Natalka. Given that it is known that GluPBC cells drive respiratory rhythm, I guess you are showing (i) the stimulation of respiratory rate that you would expect: i.e., confirmation of the method; (ii) it is capable of overcoming opioid-induced inhibition (i.e., this is the unknown before you did the experiment). However, it will be hard to target glutamate cells with a view to translation. Any thoughts? Also was the effect only on rate (i.e., any effect on diaphragm amplitude? Thanks, Richard

    • Natalka Parzei says:

      Hello Richard, thank you for your question. Yes, I would say that the purpose of my work is two-part to confirm that we can use chemogenetic techniques to activate GluPBC cells and that doing so would increase respiratory rate, as well as to then use this activation to overcome opioid-induced respiratory depression. I agree that direct translation of this work would be difficult since glutamatergic cells are widespread within the brain, and so targeting GluPBC cells particularly in humans is a tall task. I believe my work acts more as a knowledge bridge to help guide further therapeutic direction. Knowing whether or not stimulating the pre-Bötzinger complex can reduce respiratory depression can then direct research into targeting this region for preventing overdose. As for the effects on respiration seen, I have noticed changes in diaphragm amplitude as well, however I am in the process of analyzing those results so I don’t have amplitude data at the moment.

  • Tereza Martinu says:

    This is very interesting, Natalka. I am wondering why the DREADD-transformed mice had a CNO-induced increase in respiratory rate even without fentanyl? I initially thought that this CNO receptor activation would only counteract the effects of opioids but it seems that it has an effect at baseline? Could you please explain? Thank you.

    • Natalka Parzei says:

      Hello Tereza, thank you for your interest and great question. Since CNO acts on the inserted DREADD receptors, whereas fentanyl acts on µ-opioid receptors, effects of CNO are not directly linked to fentanyl or µ-opioid receptor activation. While both drugs may act on the same cell, they are not acting on the same receptors. Furthermore, mice are anesthetized at the time of recordings, so baseline respiratory rates are greatly decreased compared to an awake mouse. CNO stimulation in this case is increasing the respiratory rate in the context of depression caused by isoflurane. However, the pre-Bötzinger complex provides inspiratory drive for breathing in general, so stimulating the region even in awake mice would likely result in increased respiratory rate since our breathing can increase above baseline rates in normal contexts as well. Through this project, we aim to determine if the increase in respiratory drive provided by CNO activation of DREADDs is sufficient to prevent the depression caused by fentanyl.

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