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Histamine is one of the best-characterized pruritogens in humans. It is known to play a role in pruritus associated with urticaria as well as ocular and nasal allergic reactions. Histamine mediates its effect via four receptors. Antihistamines that block the activation of the histamine H1 receptor, H1R, have been shown to be effective therapeutics for the treatment of pruritus associated with urticaria, allergic rhinitis, and allergic conjunctivitis. However, their efficacy in other pruritic diseases such as atopic dermatitis and psoriasis is limited. The other histamine receptors may also play a role in pruritus, with the exception of the histamine H2 receptor, H2R. Preclinical evidence indicates that local antagonism of the histamine H3 receptor, H3R, can induce scratching perhaps via blocking inhibitory neuronal signals. The histamine H4 receptor, H4R, has received a significant amount of attention as to its role in mediating pruritic signals. Indeed, it has now been shown that a selective H4R antagonist can inhibit histamine-induced itch in humans. This clinical result, in conjunction with efficacy in various preclinical pruritus models, points to the therapeutic potential of H4R antagonists for the treatment of pruritus not controlled by antihistamines that target the H1R.

The lung is a complex tissue comprising many different cellular elements, including smooth muscle, both airway and vascular; vascular endothelium; respiratory epithelium; mucus-secreting cells; nerves; and connective tissue cells. The purpose of this review is to examine the evidence that histamine H2 receptors which may be present on these cells making up lung tissue have a potential to modify lung function. One of the major difficulties with such a review is the variety of different models that have been used to study histamine-mediated effects in the lung. Furthermore, it will become apparent that there are very great interspecies differences in the actions of histamine on lung tissue.

The brain is one of the last organs in which histamine receptors have been identified. This is not surprising in view of the slow emergence of the idea that the amine has an important role in neurotransmission in the CNS.

Histamine is a recently admitted neurotransmitter in the brain, and few drugs are available which selectively modify histaminergic neurotransmission for either research or, possibly, therapeutic purposes.

Histamine was discovered independently from two sources in the first decade of this century by KUTSCHER (1910) and by WINDAUS and VOGT (1907). WINDAUS and VOGT prepared histamine synthetically by the decarboxylation of histidine whereas Kutscher identified histamine as a base in ergot. Histamine is so called because the Greek word HISTOS means tissue and BARGER and DALE (1910) isolated the amine from guinea-pig intestinal tissue. Following the discovery of histamine in mammalian tissue, there was an extensive study of its biological effects by DALE and LAIDLAW (1910,1911), who noted the parallel between the actions of histamine in animals and the response of an animal to a foreign protein, normally inert, but to which the animal had been sensitised by prior injection. DALE and LAIDLAW (1919) also demonstrated that it was possible to produce shock in animals by the injection of histamine. DALE (1913) and SCHULTZ (1910) both independently demonstrated an anaphylactic reaction in isolated smooth muscle, following the original description in whole animals of the anaphylactic reaction to foreign protein by PORTIER and RICHET (1902).

The mast cell is centrally involved in the immunopathology of acute allergic and inflammatory disease (Pepys and Edwards 1979). These cells are widely distributed in the human body, but are found at the highest concentrations in those areas which come into direct contact with foreign substances, namely in association with blood vessels and nerves in the loose connective tissue of the bronchi, conjunctiva, gut, ear, nose, throat and skin. As such, they are uniquely placed to participate in a variety of allergic disorders and have been incriminated in the aetiology of asthma, rhinitis, conjunctivitis and inflammatory diseases of the gut and skin (Pepys and Edwards 1979).

The ralationships between SAMe and histamine are evident on at least one level: namely that SAMe serves as the methyl donor in the methyltransferase system that seems to represent the main catabolic pathway of endogenous brain histamine.

Antihistamines that powerfully and selectively inhibit certain effects of histamine have been known for over 25 years. The effects of histamine that they inhibit are contractile actions on the smooth muscle of the gut, uterus and bronchioles and capillary permeability responses. Some other effects of histamine are highly resistant to these antihistamines and they include stimulation of gastric secretion, relaxation of rat uterus and positive inotropic effects on isolated atria (Loew, 1947; Ashford et al., 1949; Dutta, 1949; Trendelenberg, 1960). Indeed, it has been demonstrated that gastric secretion induced by histamine is enhanced rather than diminished by antihistamines, including mepyramine (Wood, 1948) and triprolidine (Green, 1953), perhaps in consequence of histamine release (Chap. 34, Sect. CIL). Compounds that selectively inhibit histamine-induced gastric secretion and other effects of histamine resistant to the earlier antihistamines were first reported only in 1972 by Black and colleagues. They are referred to as antagonists at H2 receptors, in distinction from the earlier antihistamines whose inhibitory effects at low concentrations characterised a histamine receptor for which Ash and Schild in 1966 had suggested the symbol H1. The distinction between H1 and H2 receptors is already well characterised by studies both of selective agonists (Ash and Schild, 1966; Black et al., 1972) and antagonists (Black et al., 1972, 1973, 1975).

The mast cells are connective tissue cells characterized morphologically by the presence in their cytoplasm of numerous metachromatic granules and biochemically by their high content of heparin and histamine. The relationship between mast cells and histamine was firmly established by the fundamental papers of Riley. West and co-workers (Riley, 1953 a, b; Riley and West, 1953; Cass, Riley, West, Head and Stroud, 1954) and is dealt with in detail by Riley and West in this volume. Besides heparin and histamine, Benditt, Wong, Arase and Roeper (1955) showed that the mast cells contain also 5-hydroxytryptamine and Bhattacharya and Lewis (1956) showed that 5-hydroxytryptamine is released from rat tissues perfused with compound 48–80. It seems of interest to call attention to the fact that the role of histamine, heparin and 5-hydroxytryptamine is, up to now, completely unknown and that there is not yet any evidence that the mast cells deliver to the blood or tissues any of these substances under normal conditions. Notwithstanding, the papers referred to above, which suggest that the mast cells can act as a source of heparin, histamine and 5-hydroxytryptamine, have opened a wide field of approach to the study of mast cell physiology. In the present chapter, an attempt will be made to gather and analyze the many papers that have been published in the last years concerning the phenomenon of histamine liberation from the mast cells, with emphasis on the behavior of these cells in anaphylaxis. As we are concerned more with experimental details than with ideas, references will preferentially be made to original work rather than to reviews.

Inflammation is a complex process involving many biochemical changes with the participation of several mediators (Menkin, 1956; Rajka, 1959; Ungar, 1952). Meier (1959) and Meier et al. (1956) have recently discussed the biochemistry of the inflammatory process and its causal connections in an excellent review. Since a number of factors should be considered, it is difficult to speak of the role of a single mediator in the development of inflammation. It has been demonstrated that histamine plays an important role, but its action could not account for the whole set of events (Haas, 1951; Feldberg, 1954; Rocha E Silva, 1955). Yet, thanks to the availability of histamine liberators we may at present discern the part played by histamine better than in the past. The function of any naturally occurring agent can be better recognized by eliminating it from the organism in order to gain insight into its real physiological tasks. This method has rendered excellent service in the fields of vitamins and hormones where it has long been in use. Feldberg (1956) reviewing the mediators participating in the development of the inflammatory processes stated: “Nowadays we have the possibility of depleting a tissue of its histamine. Unfortunately this has so far been achieved only in some species and in some tissues, but by comparing, as Zweifach has done, the inflammatory vascular reaction in a normal and in a histamine-depleted tissue, we might perhaps obtain more precise information about the role of released histamine in the histamine-like vascular reactions of inflammation.”

Through the discovery of the high histamine content of the mast cells of Ehrlich, the decade 1950–1960 has seen a fresh orientation of knowledge concerning the location of histamine in blood and tissues. Looking back on events, it is now apparent that several independent lines of research were converging on this common point. In Scotland, Riley (1952; 1953 a; 1953 b) had traced a fluorescent histamine liberator (stilbamidine) to its target in the mast cells of the peritoneum of the rat, and with West (1952; 1953) had provided the first pharmacological correlation between mast cell content and histamine value for a number of tissues including human skin rich in mast cells. In Brazil, Mota et al. (1953) using a more specific histamine liberator (compound 48/80) had noted its characteristic disruptive effects on rat mast cells. Meanwhile, in the United States, Graham and her colleagues (1952) had traced the histamine in human blood to the few basophils or blood mast cells which are normally present; later (1955) they confirmed the correlation between histamine values and mast cell content in tissues.