Insomnia fueled post incoming -
I should point out that the throat should be very prone to collapse indeed if the one opiate causes paralysis, therefore these are somewhat strange models because you're using an agent that might either cause an increase breathing drive or possibly throat muscle tone in essentially a model of sleep apnea, though not all animals might have complete throat collapse with loss of muscle tone.
My pondering is, are these drugs solely increasing respiration drive - the excitability in the part of the brain that that controls breathing (as it seems there is a lot of 5-HT4 in the respiratory control center) OR is this a mechanism related to obstructive sleep apnea related breathing depression (throat collapse)? I'm curious as to whether this benefit we see with these agents could be more related to treatment of loss of muscle tone- obstructive sleep apnea (rather than respiratory drive related central sleep apnea) but what partly dispels this pondering is that the one opoid appears to cause paralysis? And therefore the chance that the elevation of blood oxygen being due to alleviation of sleep apnea with the serotonergic agent isn't likely because with the paralysis induced by the opiate the throat should still be as collapsed as ever? But it is the serotonergic system that helps regulate the paralysis during REM sleep, and other serotonergics (Mirtazapine, a 5-HT3 antagonist) are being investigated for obstructive sleep apnea. Does 5-HT3/4 overlap the areas that govern muscle tone and the related serotonergics being used might help regain throat muscle tone and therein lies some of the breathing improvements?
Strange to use etorphine in the one study, makes it hard to separate this increase in blood oxygen levels being from an increase in respiratory drive (detection and correction of high carbon dioxide levels) from a treatment of muscle tone loss/sleep apnea, as the serotonergics have found use in the treatment of obstructive sleep apnea. Though maybe they used etorphine just for this purpose- to ensure throat muscles were paralyzed throughout? But if the breathing depression can be overcame with the serotonergic then surely the throat collapse could be overcame as well? Confusing.
ANYWAYS.
Sleep apnea carries most of the same characteristics as respiratory depression due to opioids (you're essentially looking for elevated carbon dioxide and low blood oxygen).
The idea behind obstructive sleep apnea is during REM sleep our muscles lose tone and when our throat collapses because of this it is harder to breathe, if this is milder it is known at upper airway resistance syndrome. I hypothesize that when using opioids and similar substances (anything that decreases excitability likely) the throat is more apt to lose muscle tone and collapse, thus being a drug induced sleep apnea / upper airway resistance syndrome essentially. This will lighten up sleep (the body attempts to increase wakefulness enough to breath normally) and make for pathological sleep deprivation.
Mirtazapine is being investigated for the treatment of obstructive sleep apnea (where the throat collapses, and NOT central sleep apnea, where there is reduced breathing drive) it is a 5-HT3 antagonist as well, I wonder what else it had affinity for. It is supposedly effective for sleep apnea because it is serotonin that regulates the throat's muscle tone.
If these drugs increase breathing drive they should be a treatment for central sleep apnea as well as maintaining optimum blood oxygen levels when we sleep even for somebody without oxygen dips severe enough to be classified as central sleep apnea, but if they do not cause wakefulness they would likely be a partial treatment for obstructive sleep apnea, they should stimulate breathing enough to keep the oxygen levels fairly high and keep sleep regenerative, especially as we lose breathing drive with age or as the heart begins to lose efficiency and we need higher blood oxygen levels to compensate.
If the 5-HT4 serotonin is abundant in the respiratory drive center in the brain then I wouldn't be surprised if this was somehow linked into sleep/sleep apnea, our muscles paralyze during sleep so we don't act out our dreams and hurt ourselves but we must maintain enough muscle tone to still breathe and sometimes swallow (so we don't choke on our saliva). Would love to see these 5-HT4 drugs tried out for sleep apnea, both obstructive and central. Maybe they affect throat muscle tone as well.
But they should be an option for preventing apnea of prematurity in babies, normally caffeine is used (though maybe that's outdated information) to increases breathing drive but I shudder to think what messing with a child's adenosine/sleep like that could do to them long term.
