Histamine - Triple Response
How Histamine Induces Three Cardinal Circulatory and Nerve Responses of Skin
Histamine. A friend and a foe. An amazing molecule that was first isolated by English scientists George Barger and Henry H. Dale in 1910. They were researching ergot. A plant fungus used to manage postpartum bleeding. In 1911 they isolated histamine from the animal tissues as well. In 1913 the name Histamine was coined. Histo meaning tissue and amine for its chemical group.
Originally histamine was thought to be a tissue hormone or an autocoid. The reason for this thinking was that there didn’t seem to be a gland that produced histamine. New research has now revealed that histamine is also a neurotransmitter.
It might surprise you to learn that plants contain histamine as well. Stinging nettles, for example, have histamine in their tiny hairs. Brushing up against these hairs can cause itching and swelling, and histamine is partly to blame. In fact, histamine is also present in the venom of many bees and wasps, which is why stings can be so painful and itchy.
Figure 1: animals, some plants, bees, and some wasp species contain histamine. Stinging nettle for example has histamine in its hair. Similarly, some bee and wasp species have histamine in their sting. In humans mast cells contain the largest reservoir of histamine.
An Overview of the Functions of Histamine
Histamine plays a surprising number of roles in the human body, acting as both a local hormone and a neurotransmitter. Here's a quick rundown of its key functions and effects:
Immune Response and Inflammation:
Defense Mechanism: Histamine is a key player in the immune response, helping to defend against pathogens. It increases blood vessel permeability, allowing immune cells to reach infection sites.
Allergic Reactions: When the immune system overreacts to harmless substances or allergens, histamine release triggers allergy symptoms like itching, swelling, runny nose, and bronchoconstriction (tight airways) in asthma.
Digestive System:
Gastric Acid Secretion: Histamine stimulates the production of stomach acid, aiding digestion.
Nervous System:
Sleep-Wake Cycle: Histamine in the brain regions helps regulate sleep and wakefulness.
Learning and Memory: Some research suggests histamine might play a role in learning and memory processes.
Other Effects:
Vasodilation: Histamine can cause blood vessels to widen, affecting blood pressure and blood flow.
Pain: Histamine interacts with pain receptors, contributing to the stinging or burning sensation associated with allergies and inflammation.
Orgasm: Emerging research suggests histamine might play a role in intensifying sensations and blood flow during sexual arousal.
Histamine Storage
Most histamine in tissues is present/sequestered in mast cells and is in bound form. This bound form is inactive. Basophils also contain histamine. Mast cells are present abundantly in tissues susceptible to injury. Nose, mouth, feet, internal surfaces of our body, blood vessels, and more. Blood vessels at the pressure points and folds of the body have especially a larger number of mast cells. Histamine is also present in the nervous system tissue. Cells of the funds of the stomach called enterochromaffin-like cells also contain histamine.
Triple Response
Today my focus is to present the molecular mechanism of triple response produced by histamine.
Triple response is a cutaneous response that can be elicited by scratching/firmly stroking on the skin. There is an initial red line, then a flare around this line, and finally a wheel /edema appears. The red line appears within 15 seconds. Flare appears within 15-45 seconds. And the wheel or edema appears within 1-3 minutes.
Let’s discuss the cellular mechanisms that produce this series of responses and how histamine drives them.
Histamine is the inducer of the triple response. Triple response also can be observed with the intradermal (in the skin layers) injection of histamine. Three different cell types are involved in these reactions.
Redness
Initial stroking of the skin cause histamine release from the mast cells. Histamine dilates small blood vessels. Histamine binding to the endothelial cells triggers the production of vasodilator substances in these cells. These substances include nitric oxide (NO). NO is a major vasodilator. Endothelial nitric oxide exits the cells and moves to the middle layer of the blood vessel wall. This layer called tunica media contains smooth muscles of the blood vessel and helps regulate blood vessel diameter. NO results in relaxation of these smooth muscles resulting in vasodilation. NO performs this action by reducing free calcium in the smooth muscle cells and by also reducing further influx of calcium into the smooth muscle cells. Calcium is an important ion needed for the muscle contraction. Lack of free calcium inside the muscle cells causes these muscle cells to be relaxed resulting in vasodilation.
Figure 2: histamine causes the smooth muscles of the blood vessels to relax. Result is vasodilatation. Which in turn leads to local redness. On a systemic levels this can cause a fall in blood pressure.
Flare
Histamine acts on the sensory nerve endings leading to the release of substance P (SP) from these never endings. Substance P in turn triggers local immune cells. Immune cells start releasing inflammatory cytokines that results in characteristic redness of the flare to appear.
Figure 3. histamine acts on the local sensory nerve endings. Which release substance P (SP). SP in turn acts on the local immune cells. Resulting inflammation causes the flare around the area of histamine injection or release from the mast cells.
Wheel/Edema
Another function of histamine on endothelial cells is to activate their actin and myosin proteins. These proteins are contractile units of the endothelial cells. Yes, endothelial cells contract like tiny little muscles. They shrink. Gaps appear between the shrunken cells. These gaps allow fluids, proteins, and other substances to extravasate/leak out of the blood vessels, especially from venules that are thin walled. This fluid accumulates in the local tissue to form characteristic wheel/edema.
Figure 4. histamine acts on the actin and myosin machinery of the endothelial cells. This results in shirking of the endothelial cells (B). Gaps between these cells allow fluids and substances to extravasate in the tissue resulting in wheel or hives.
Clinical Pearls
Histamine triple response is produced primarily when histamine binds with H1 receptors. Hence, adequate doses of H1 blockers can help prevent most of these effects. However, H2, and H3 receptors may be involved as well.
Similar response can be elicited by intradermal injection of histamine-liberators for example morphine.
Appropriate antigens can also elicit triple response by inducing mast cells to release histamine.
Triple response is primarily invoked by H1 receptors, hence, H1 receptor blockers can be used to manage this response.
List of references
Histamine - Wikipedia
https://en.wikipedia.org/wiki/Histamine#:~:text=can%20be%20diagnosed.-,History,%2C%20yielding%20%22tissue%20amine%22.
Histamine | Description & Facts | Britannica
https://www.britannica.com/science/histamine
Histamine and its receptors - PMC
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760721/
Histamine induces IL-6 production by human endothelial cells - PubMed
https://pubmed.ncbi.nlm.nih.gov/7955543/
Histaminergic neurons in the tuberomammillary nucleus as a control centre for wakefulness - PubMed
https://pubmed.ncbi.nlm.nih.gov/32744724/
The effects of histamine and some histamine-like agonists on blood pressure in the cat. - PMC
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1666775/
Histamine and histamine intolerance - PubMed
https://pubmed.ncbi.nlm.nih.gov/17490952/
Histamine, histamine receptors, and neuropathic pain relief - PMC
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012972/#:~:text=In%20neuropathic%20pain%2C%20histamine%20released,of%20hypersensitivity%20following%20nerve%20injury.
Neuroanatomy and function of human sexual behavior: A neglected or unknown issue? - PMC
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908863/
Control of gastric acid secretion: the gastrin-ECL cell-parietal cell axis - PubMed
https://pubmed.ncbi.nlm.nih.gov/11246041/#:~:text=Gastric%20acid%20secretion%20is%20under,parietal%20cells%20to%20secrete%20HCl.
Histamine's Sleep Role
https://chat.openai.com/c/1f85d745-e673-4776-9f72-f67624a3cfe2
Contact urticaria due to the common stinging nettle (Urtica dioica)--histological, ultrastructural and pharmacological studies - PubMed
https://pubmed.ncbi.nlm.nih.gov/2025924/#:~:text=The%20mean%20histamine%20and%20serotonin,ng%20and%2033.25%20pg%2C%20respectively.
histamine triple response - Google Search
https://www.google.com/search?q=histamine+triple+response&oq=histamine+triple+response&gs_lcrp=EgZjaHJvbWUyCQgAEEUYORiABDIICAEQABgWGB4yCAgCEAAYFhgeMg0IAxAAGIYDGIAEGIoFMg0IBBAAGIYDGIAEGIoFMg0IBRAAGIYDGIAEGIoF0gEIMzQ1NmowajeoAgCwAgA&sourceid=chrome&ie=UTF-8
Triple response Definition and Examples - Biology Online Dictionary
https://www.biologyonline.com/dictionary/triple-response
I appreciate this written work. Thank you, Dr. Mobeen. I have been reading a lot about mast cell activation syndrome these past 2 years.❤️🙏
This is pure gold,thank-you.