Peripheral Neuronal Mechanism of Itch: Histamine and Itch

The study of the physiological effects of histamine has a long history, spanning more than a century. Drugs that target histamine have been very successful, and even those not in the medical profession recognize that “antihistamines” are effective treatments for the symptoms of allergies and rhinitis. Histamine research has also spawned a wealth of scientific literature, and a search of the term “histamine” in PubMed yields almost 80,000 references. Even back in 1953, Sir Henry Dale himself said in his memoirs that histamine “…is by now almost too familiar” (Dale 1953, p. 119). Yet new functions are still being uncovered, and this is prompting the development of new drugs that target histamine. Histamine results from the decarboxylation of histidine, and was first described synthetically by Windaus and Vogt in 1907 (Windaus and Vogt 1907). Shortly thereafter, Dale and colleagues found that it was a natural constituent of ergot, which was potent in inducing contraction of certain muscles (Barger and Dale 1910; Dale and Laidlaw 1911). Further work suggested that the effects of histamine were similar to those seen with anaphylaxis (Dale and Laidlaw 1911). Interestingly, Dale did not use the obvious name, histamine, as he explained in his memoirs (Dale 1953), because it was claimed to be too similar to a trademark; Dale instead used the chemical name β-iminazolylethylamine. In addition to this, Dale took great care in his early work not to suggest that histamine was actually involved in normal physiological processes: “…a possibility that was almost clamouring to be recognized,” in his own words (Dale 1953, p. 337). The statement that histamine played a physiological role had to await the proof of its existence as a natural component of tissue. This was hinted at by early work (Barger and Dale 1911; Abel and Kubota 1919) but was not shown conclusively until 1927 (Best et al. 1927). By 1929, in his Croonain Lectures, Dale readily acknowledged that histamine was a normal constituent of many tissues (Dale 1929). We now know that histamine is produced by many cell types and can be stored by cells such as mast cells, basophils, enterochromaffin-like cells, and neurons. Release from these cells mediates many of the functions that we now intimately associate with histamine, i.e., allergy, gastric acid secretion, neuron transmission, anaphylaxis, etc. Early work linked histamine with responses to trauma in the skin. Injury, firm stroking of the skin, or many other stimuli cause a triple response of local vasodilation, local edema, and flare, which were described in work by Sir Thomas Lewis and coworkers and summarized in his book, (Lewis 1927). Lewis recognized that injury to the skin liberated a substance that resembled, at least in its action, histamine. He carefully termed this the H-substance because there was no proof that histamine existed in skin, although it was clear he suspected the agent was histamine. He states, “…it is difficult to refrain from stating without reserve the simple conclusion that the vasodilator substance considered and the H-substance are one and the same, and that this substance is histamine” (Lewis 1927, p. 235). Others were not as cautious. In his 1929 Croonain Lectures, Dale discussed this in depth and concluded that “…the suggestion was obvious that…Lewis’ H-substance, was histamine itself, not newly formed…but already existing…”, although he acknowledged that final proof required the substance to be isolated (Dale 1929, p. 1235).