Histamine: intended functions and mast cell symptoms

Histamine is derived from the amino acid histidine, which is found through the human body.  It is usually stored inside cells or immediately degraded by enzymes.  (One of the enzymes that does this is called n-methyltransferase, and the remaining product of histamine breakdown from this activity is called n-methylhistamine.  This is the molecule detected in 24 hour urine tests.)  Histamine is produced predominantly by mast cells and basophils. 

Histamine is a small and versatile molecule that can hold a charge, enabling it to participate in many roles.  Histamine has protective effects, including seizure suppression, and prevention of drug sensitization.  It is also thought to be important in the loss of memory and learned skills.  It performs its functions by interacting with histamine receptors on various cells through the body.  There are four known histamine receptors, called H1, H2, H3 and H4.

H1 receptors are found in the central nervous system, including significant numbers in various regions of the brain.  When histamine binds the H1 receptors in the brain, it helps to regulate the sleep-wake cycle.  Contrary to popular belief, histamine actually increases wakefulness.  The H1 receptors in the brain also regulate body temperature, pain perception, appetite, mood (including anxiety/depression), learning, memory and secretion of hormones, including norepinephrine. 

H1 receptors are also found in the peripheral nervous system and endothelium (the cells that line blood and lymphatic vessels.)  When histamine binds to these receptors, it causes airway constriction, difficulty breathing and dilation of blood vessels.  It also causes the separation of endothelial cells, which causes the formation of hives.  It is also largely responsible for pain and itching, as well as irritation and swelling of the nasal passages, increased secretions from local glands and sneezing.  Motion sickness is also attributed to H1 receptor activity.   

H2 receptors are found mostly on cells in the GI tract and smooth muscles in vascular tissues, where it can cause vasodilation.  Cells in the glands of the stomach release histamine, which stimulates parietal cells with H2 receptors on them.  When the receptors are stimulated, the parietal cells cause the secretion of hydrogen ions into the stomach, making it more acidic.  For this reason, H2 blockers are often marketed for indigestion and acid reflux. 

H3 receptors are found in the central and peripheral nervous systems.  They are primarily responsible for modulating the release of neurotransmitters, including histamine, acetylcholine, norepinephrine and serotonin.  Medications that block the H3 receptor increase wakefulness.

H4 receptors are found on basophils, thymus, small intestine, spleen, colon and in the bone marrow.  It is involved in signaling for immune cells to attend areas of inflammation.

As everyone with mast cell disease knows, overstimulation of histamine receptors causes a variety of symptoms. 

Overstimulation of H1 receptors causes the following:

-Flushing, itching and hives, due to stimulation of pain receptors in the skin and increased vasodilation and permeability from the lymphatic and blood vessels.

-Congestion of the nose, sneezing, airway constriction and difficulty breathing, due to increased mucus production and smooth muscle constriction.

-Irregular and painful menstruation due to smooth muscle constriction and increased estrogen.

-GI cramping, gas, diarrhea and abdominal pain, due to smooth muscle constriction.

-Rapid heartbeat and irregular heart rhythm, low or high blood pressure and dizziness/fainting, due to increased vasodilation.  These symptoms can lead to anaphylaxis.

Medications that block stimulation of the H1 receptor include diphenhydramine, cetirizine, hydroxyzine, chlorpheniramine, clemastine, cyproheptadine, desloratadine, loratadine, fexofenadine, levocetirizine, meclizine, mirtazapine, promethazine, and rupatadine. 

Overstimulation of H2 receptors causes the following:

-GI cramping, gas, diarrhea and abdominal pain, due to gastric acid secretion.

-Increased levels of signaling molecules that increase mast cell secretion of mediators.

Medications that block stimulation of the H2 receptor include cimetidine, famotidine, nizatidine and ranitidine. 

Overstimulation of H3 receptors causes the following:

-Dizziness/fainting, headache, nausea, vomiting, irregular sleep/wake cycle, brain fog, irregular body temperature, dysregulation of appetite, difficulty in movement, and loss of memory and learned skills.  All of these are due to excess neurotransmitter release.

Overstimulation of H4 receptors is thought to possibly increase production of blood cells and mast cell secretion.  This is not yet definitive.