Any time I
would get into a reasonable rhythm, something would change and I would have to
start all over again. Other symptoms
have been harder to deal with in some ways, but it is safe to say that being so
tired has caused me more grief than anything else. It is the root cause of all the myriad ways I
have lost control over my life.
I am now in
a really obnoxious cycle in which I am awake for 30 hours and then sleep for 18
hours. It is really disruptive and
disorienting. A few weeks ago, shortly
after I was released from the hospital, I decided that I would no longer try to
control my sleep. I would sleep when my
body wanted to sleep, because it wasn’t worth how sick I felt when I forced
myself to wake even when I was exhausted.
So I gave up and moved on. Some
things are just not worth fighting after so long.
Last night
while I couldn’t sleep, I did some research on why I couldn’t sleep and wrote
it up for all of you mast cell kids who also can’t sleep. SPOILER ALERT: It’s because of mast cells.
Mast cells
are found in several parts of the brain.
Just like in other places, they degranulate or secrete factors, and they
influence activity of the central nervous system. One of the ways they affect the body is by participating
in the sleep/wake cycle.
About half
of the histamine found in the brain is released by mast cells. Histamine actually increases wakefulness and
decreases sleepiness. This has been
addressed in multiple papers, but one of the most well designed experiments
involved mast cell deficient mice. These
mice were much more tired than the mice who had normal amounts of mast cells.
Histamine
activity in the brain is increased during food deprivation or starvation
conditions. This is part of why eating
regularly is important to sleep hygiene, even in the typical population. When you’re hungry at bedtime, your mast
cells tell your brain that it needs to find food that it doesn’t starve.
This same
study also showed that the number of mast cells in the brain is determined, at
least in part, but stress levels.
Chronic fight or flight type of stress, like exposure to a predator,
increased the number of mast cells. This
makes sense because you need to stay awake to fight. Social stress, like isolation, decreased the
number of mast cells.
Treatment
with H1 blocking antihistamines (Benadryl, etc) decreased wakefulness. This indicates that the sleepiness might be
due to preventing the release of histamine from mast cells. Conversely, treatment with an H3 blocker
actually made you less tired. (I can
attest to the fact that ketotifen, an H3 blocker, does in fact make me less
tired.) Treatment with substances that
prevented histamine synthesis caused sleepiness.
Prostaglandin
D2, another mast cell released factor, has been studied a lot as a regulator in
the sleep/wake cycle. Infusion of PGD2
into the brains of mice causes large and sustained increases in sleep.
PGD2
activates cells through DP1 receptors.
When these receptors are stimulated, adenosine is released into the
brain. Adenosine increases
sleepiness. Mild to moderate levels of
inflammation cause increased production and secretion of PGD2, resulting in
tiredness. However, in severe
inflammation, another molecule, PGE2, is secreted preferentially by other cells
and stimulates mast cells to release histamine.
This might explain why people who are chronically ill sleep so poorly
despite being so tired. Sleep in people with high PGE2 is fragmented and not
deep to the same extent as the general population.
References:
Saper, Clifford, et al.
Neural circuitry
engaged by prostaglandins during the sickness syndrome. Nature Neuroscience
15, 1088-1095 (2012)
Chikahisa S, Kodama T, Soya A, Sagawa Y, Ishimaru Y, et
al. (2013) Histamine from Brain Resident MAST Cells Promotes Wakefulness and
Modulates Behavioral States. PLoS ONE 8(10): e78434.
doi:10.1371/journal.pone.0078434
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