Histamine

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Histamine, or 2-(4-imidazolyl)-ethylamine, a is biogenic amine. It is synthesised through the decarboxylation of the amino acid histidine primarily in mast cells.

Itch

Itch Clinical Effects

Itch is thought to be a significant aspect of nociception. It has many similarities to pain, but generates a different behavioural response. Pain elicits a withdrawal reflex, while itch elicits a scratch reflex.

Following a stimulus resulting in itch, the individual experience itch at the site which persists briefly after the stimulus is removed. Following this there is a poorly localised area around the stimulus site, which when exposed to gentle touch, elicits intense itch. This is called alloknesis, and is analogous to allodynia.

There are four types of itch

1. Pruritoceptive itch, transmitted by C fibres e.g. with inflammation or skin dryness
2. Neuropathic itch, the archetypal disease being post-herpetic neuropathic pain. There is a loss of peripheral sensory neurons, which may lead to hyperactivity in the central itch-specific neurons or possibly disinhibit second order neurons.
3. Neurogenic itch, occurs without any neural pathology. For example cholestatic itch (through opioid peptides synthesised by the liver), and exogenous opioid agonism on mu receptors.
4. Psychogenic itch, such as in delusional parasitosis.

Itch Neurophysiology

Itch is transmitted by a dedicated subclass of C fibres, distinct from the polymodal C fibres involved in pain transmission. These so-called "itch neurons" have extensive terminal branching, slow conduction velocities, and a long lasting response to histamine. Itch neurons are not sensitive to mechanical stimuli.

There are no specific itch receptors on peripheral nerve endings in the skin, unlike what we see with pain. It is thought that there may be such receptors in second order neurons.

In the cerebral cortex, with itch PET imaging has shown co-activation of the anterior cingulate cortex, supplementary motor area, and inferior parietal lobe. The activation pattern is similar to that of pain, but without activation of the thalamic and somatosensory cortex.

The reason why rubbing inhibits the sensation of itch is because this stimulates myelinated A fibre low threshold mechanoreceptors. Scratching also inhibits itch though the stimulation of nociceptors.

Clinical Relevance

Pruritis is seen in many medical conditions such as CKD, lymphoma, HIV, post-herpetic neuralgia, multiple sclerosis, cholestasis, and certain dermatological conditions.

Itch is a common side effect of morphine. This is not an allergic reaction, but rather due to activation of mu receptors. Kappa and delta agonism does not evoke a similar response. Consequently, naltrexone an opioid receptor antagonist, reduces the itch from morphine, but histamine antagonists have no effect.

Histamine Effects

Histamine is a hydrophilic vasoactive amine. It is a potent vasodilator being involved in the acute inflammatory response and plays a key role in many allergic reactions. It is involved in gastric acid section. It also is involved in neuromodulation in the central nervous system.

Mast cells are recruited to sites of tissue injury, and are also resident in most tissues. They release proinflammatory mediators, including NGF upon activation.

Triple Response of Lewis

The "triple response of Lewis" is a cutaneous response that occurs from the firm stroking of the skin. The same response occurs with the intradermal injection of histamine.

1. Red spot, appears within a few seconds caused by capillary vasodilation.
2. Flare, develops slowly as a redness in the surrounding area due to arteriolar dilation mediated by axon reflex.
3. Wheal, develops within 1-2 minutes caused by exudation of extracellular fluid from capillaries and venules.

Role in Pain

Histamine stimulates various nerve endings. In the epidermis it causes itching, and in the dermis it causes pain with or without itching.

In the superficial layers of the skin, the release of histamine from mast cells is a pruritogenic event through the bending of H1 receptors in the terminal membranes of a special subgroup of C-afferent fibres.

Histamine causes the release of prostaglandin E2 which sensitises pain receptors (see NSAIDs). It plays a role in acute inflammation related to mast cell degranulation, but it has an uncertain role in chronic inflammation. At low levels it may cause an itching sensation, and pain at higher levels.

Histamine Receptors

The action of histamine is mediated by three receptors

1. H1 receptors play a role in bronchospasm (inhibited by H1 antagonists)
2. H2 receptors mediate facial cutaneous vasodilation and simulate gastric acid secretion (inhibited by H2 antagonists)
3. H3 receptors in animal models are found on nerve endings. They mediate the inhibition of neurotransmitter release. This is thought to involve modulating calcium entry in nerve cells.

The greatest concentration of histamine receptors are found in the skin, lungs, and gastrointestinal tract. Important cells that store and release histamine are mast cells, basophils, and CNS neurons.