I'm trying to sort this out but I'm not sure I understand it correctly. And my brain hurts
In the last Nightwalkers publication there is an article that H3 receptor antagonists may be helpful for reducing RLS symptoms.
Now, I have wondered for quite some time if my proton-pump inhibitor therapy (meds to block production of stomach acid - 40 mg pantoprazole a day, since I suffer from diaphragmatic hernia) has something to do with my restless legs, since my RLS began shortly after I started the PPIs. (Although I have a lot of relatives with RLS not taking PPIs.) Earlier on I assumed that the mechanism may be that the reduced stomach acid would cause some problems in the uptake of some nutritients, and possibly with some increase in some bacterial levels (even though I know I have no helicobacter bacteria, I checked this about a year ago). Wikipedia reads "Gastric acid is important for breakdown of food and release of micronutrients, and some studies have shown possibilities for interference with absorption of iron, calcium, magnesium, and Vitamin B12. With regard to iron and vitamin B12 the data are weak and several confounding factors have been identified" (https://en.wikipedia.org/wiki/Proton-pump_inhibitor). And we all know the connection between RLS, iron and vitamin B12.
In any case there was an interaction between the PPIs and my RLS medication (oxycodone) due to both being metabolized by the same enzyme CYP3A4 (I posted something about that here). Now, I underwent fundoplication surgery 3 weeks ago, and I'm suffering from some presumed side effects of tapering the PPIs. I started to read more about it and found another possible connection between RLS and PPIs: Histamine levels. (Having read the Nightwalkers article I felt a "click" when I read about histamines and PPIs.) What's the connection? I'm not sure. This is highly theoretical. Most likely I'm wrong. I'll still make a fool out of myself and present it. Here we go.
PPI therapy increases the histamine levels, the histamine activates the H3 receptors and this in turn reduces the production of dopamine and GABA.
OK, why should this be true?
Histamine has a role in sleep-wake regulation. "Histamine is released as a neurotransmitter. The cell bodies of histamine neurons are found in the posterior hypothalamus, in the tuberomammillary nuclei. From here, these neurons project throughout the brain, including to the cortex, through the medial forebrain bundle. Histamine neurons increase wakefulness and prevent sleep." (https://en.wikipedia.org/wiki/Histamine)
Continued from Wikipedia:
There are 4 receptors:
- The H1 receptor has a function on the CNS, affecting sleep-wake cycle, body temperature, nociception, endocrine homeostasis, appetite, mood, learning, and memory.
- The H2 receptor: Primarily involved in vasodilation. Also stimulate gastric acid secretion.
- The H3 receptor: Decreased neurotransmitter release: histamine, acetylcholine, norepinephrine, serotonin
- The H4 receptor: Plays a role in mast cell chemotaxis.
As for the H3 receptors: "Histamine H3 receptors are expressed in the central nervous system and to a lesser extent the peripheral nervous system, where they act as autoreceptors in presynaptic histaminergic neurons, and also control histamine turnover by feedback inhibition of histamine synthesis and release. The H3 receptor has also been shown to presynaptically inhibit the release of a number of other neurotransmitters (i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to dopamine, GABA, acetylcholine, noradrenaline, histamine and serotonin. [...] The H3 receptor is coupled to the Gi G-protein, so it leads to inhibition of the formation of cAMP. Also, the β and γ subunits interact with N-type voltage gated calcium channels, to reduce action potential mediated influx of calcium and hence reduce neurotransmitter release. H3 receptors function as presynaptic autoreceptors on histamine-containing neurons." (Wikipedia, https://en.wikipedia.org/wiki/Histamine_H3_receptor).
So in english, the H3 receptor is a histamine level regulator: Its function is to make sure that the higher the histamine levels, the lower the histamine production. Right. Blocking the H3 receptor will increase the release of other neurotransmitters like dopamine and GABA. (Hey, I did ask what's the connection between GABA and RLS. We know that GABA helps, but why?)
So, high histamine levels may prevent sleep and and reduce the amount of GABA and dopamine produced.
What puzzles me: It is known that antihistamines like Benadryl (Diphenhydramine) are known to exacerbate RLS symptoms. Hmm. "Diphenhydramine is an inverse agonist of the histamine H1 receptor." (https://en.wikipedia.org/wiki/Diphenhydramine). So, Diphenhydramine will decrease the effect of the H1 receptor - it makes us drowsy. Why are RLS symptoms exacerbated by this? "Diphenhydramine has also been shown to inhibit the reuptake of serotonin." Now, that sounds familiar. Maybe the RLS interactions comes from the SSRI action and not from the histamine H1 action?
OK, what's the connection to PPIs?
"PPI therapy leads to diminished acid secretion, diminished antral D-cell release of somatostatin, consequent increased G-cell release of gastrin and hypergastrinemia. This causes oxyntic cell hyperplasia, increased parietal cell mass, glandular dilatations and stimulation of enterochromaffin-like (ECL) cells to release chromogranin and histamine, raising their concentrations in serum.
[...]
PPIs inhibit acid secretion, leading antral G cells to release gastrin, causing hypergastrinemia. Gastrin, in turn, binds to gastric mucosal ECL cells, causing them to release chromogranin, histamine and other substances. The acid-secretory effects of gastrin are inhibited by PPI[...]. In most patients, PPI-induced elevations in serum gastrin are moderate (50–400 pg/ml) and normalize when the drug is stopped. " (http://www.medscape.com/viewarticle/730747_6).
The thing that puzzled me at first is that PPIs increase the histamine level, while histamines should activate the H2 receptors and produce gastric acid. however, "Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, or, more commonly, the gastric proton pump) of the gastric parietal cells.[3] The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion." (https://en.wikipedia.org/wiki/Proton-pu ... _of_action). Basically gastric acid is a result of a chain of biochemical reactions. The H2 stimulation is early in the chain, while the PPIs block a later stage in that chain. OK.
So, there you have it.
PPIs increase histamine production.
Histamine levels induce wakefulness and activate the H3 receptor.
The H3 receptor is responsible for a reduced production of dopamine and GABA.
Sounds sensible? Please chime in. Or make sure to crush my argument if I'm wrong.
Regards, Thomas