Histamine is a vasoactive amine (a.k.a. a biogenic amine). It acts via a family of G protein-coupled receptors (histamine receptors H1-H4). The histamine receptors are differentially expressed, and couple to different second messenger systems. This results in context-specific effects in response to histamine release.

HIstamine is produce from the amino acid histidine by the action of histidine decarboxylase. If not stored, it is rapidly inactivated by histamine-N-methyltransferase or diamine oxidase.

As an inflammatory mediator, histamine is released from storage granules located in connective tissue mast cells, basophils and eosinophils. IgE-sensitized cells degranulate when exposed to antigen. This stimulates release of stored histamine in to the surrounding tissues, where it promotes capillary permeability allowing leukocytes and immune reaction mediators access to local tissues. Histamine is the most significant mediator of pruritus.

In anaphylaxis, the histamine surge causes extensive vasodilation which results in a rapid reduction in blood pressure.

In nasal mucous membranes, histamine release causes increased vascular permeability which in turn allows fluid egress from the capillaries to surrounding tissues producing the allergic symptoms of a runny nose and watery eyes. Sneezing associated with allergy is caused by histamine-induced stimulation of sensory neurons in the nasal cavity.

Histamine is also involved in regulating physiological function in the gut where it is produced in the enterochromaffin-like (ECL) cells of the stomach. It acts locally on the histamine H2 receptor on parietal cells to increase gastric acid secretion. Antagonism of H2 receptors is the molecular mechanism of action of the antacids famotidine and cimetidine.

Lastly, histamine is know to have neurotransmitter activity. Histaminergic neurons in the tuberomammillary nuclei of the posterior hypothalamus project throughout the brain. Histamine signals from these cells control a variety of processes including arousal, learning, memory, sleep and energy balance, with histamine notably increasing wakefulness and preventing sleep. This is why older brain-penetrant antihistamines (antagonists targeting the H1 receptor) cause drowsiness. Histamine in the CNS is principally degraded by histamine-N-methyltransferase.

Mastocytosis is a mast cell activation disorder characterised by a proliferation of mast cells and excess histamine release. Sufferers of this condition are prone to itching, hives, anaphylactic shock and excess gastric acid production. In rare cases the disease is aggressive and can result in organ failure related to mast cell infiltration. Some patients develop malignant mast cell leukemia, and mast cell sarcoma. Symptomatic relief is multi-targeted: antihistamines, mast cell stabilisers, proton pump inhibitors, epinephrine, beta 2 agonists, corticosteroids, antidepressants and calcium channel blockers all target the various symptoms of the condition, but it cannot be cured. Intensive (chemo)therapy (with or without allogeneic stem cell transplantation) is considered in cases of malignant mast cell disease. Current and future treatment options are reviewed by Molderings et al. (2016) PMID: 27132234.