br Introduction The role of
Introduction The role of histamine in allergic responses, anaphylaxis, and gastric Hydroxyzine 2HCl sale secretion has been well described in both human and veterinary medicine. New roles for histamine and its receptors, however, have been elucidated over the last two decades (Smuda and Bryce, 2011), and novel histamine receptor antagonists have also recently been developed (Thurmond, 2010). Histamine has been shown to have an important role in many functions of the gastrointestinal (GI) tract, including neurotransmission, visceral nociception, and mucosal immunity (Peters and Kovacic, 2009, Deiteren et al., 2015). Histamine is a primary amine that is synthesized via decarboxylation of the amino acid histidine in mast cells, platelets, basophils, histaminergic neurons, and enterochromaffin cells, and then stored within intracellular vesicles (Peters and Kovacic, 2009). Mast cells, which are abundant throughout the body, but especially in the skin and GI tract, are the predominant storage site of histamine (Shahid et al., 2009). Immunological and non-immunological stimulation of histamine-producing cells triggers release of histamine. Histamine then exerts its actions via binding to four different G-protein coupled receptors (H1, H2, H3, and H4) throughout the body (Parsons and Ganellin, 2006). Histamine mediates many different physiologic responses, of which the best-known is the Type I hypersensitivity reaction. In the GI tract, histamine is involved in regulation of gastric acid production, smooth muscle motility, and mucosal ion transport (Sander et al., 2006). Histamine also has a role in mucosal defense and neurotransmission (Peters and Kovacic, 2009). Importantly, histamine is a potent mediator of inflammatory responses, inciting cytokine and chemokine release and inducing chemotaxis and adhesion molecule production (Xie and He, 2005, Shahid et al., 2009, Thurmond, 2015). Histamine receptors are dispersed throughout the body, with each individual receptor mediating unique responses. Investigation of histamine receptors has to date been limited in the veterinary literature, but these receptors have been more thoroughly explored in human medicine. In humans, histamine receptors have been demonstrated with polymerase chain reaction (PCR), Western blotting, and immunohistochemistry techniques (Sander et al., 2006). Approximately 50 years ago, it was first recognized that not all histamine receptors were alike, and that various cells expressed different histamine receptors (Thurmond, 2010). The first two receptors to be identified and categorized in humans were the H1 and H2 receptors (Thurmond, 2010), which are both widely distributed throughout the body (Thurmond, 2010). H1 receptors mediate smooth muscle contraction, particularly in the airways and GI tract, and are heavily involved in hypersensitivity reactions such as asthma (Peters and Kovacic, 2009). H1 receptors are also involved in the pathogenesis of some of the classic features of the inflammatory reaction, such as vasodilation and increased vascular permeability (Shahid et al., 2009). The best-known function of the H2 receptor is regulation of gastric acid secretion. The H2 receptor also influences intestinal secretion and neurotransmission, and has been shown to mediate both pro-inflammatory and anti-inflammatory processes in the immune response (Xie and He, 2015; Smuda and Bryce, 2011). The presence of the H3 receptor in humans was confirmed approximately 25 years ago, and the receptor was successfully cloned in 1999 (Thurmond, 2010). The H3 receptor is unique, as it controls feedback of histamine release, particularly in the central nervous system, where it modulates neurotransmitter release and acts at the presynaptic histaminergic neurons, inhibiting release and synthesis of histamine (Peters and Kovacic, 2009). H3 receptors are also involved in mucosal defense and inhibition of neurotransmitter release within the GI tract in humans (Breunig et al., 2007, Coruzzi et al., 2012).