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Whether histamine receptor distribution is altered
Whether histamine receptor distribution is altered in canine GI diseases remains unknown, but human research has documented altered histamine receptor density in certain GI diseases (Sander et al., 2006, Deiteren et al., 2015, Von Rahden et al., 2011). Additionally, a novel H4 receptor antagonist, JNJ7777120, has been shown to reduce histological inflammation and clinical signs in experimentally-induced colitis (Schirmer et al., 2015). Interestingly, the dog in our study with histologic evidence of mild gastritis had stronger mucosal staining for the H1 receptor and stronger lymphoid tissue staining for the H3 receptor compared to the dogs with normal gastric biopsies.
One limitation of our study was that all control dogs had histologic evidence of mild GI inflammation according to established WSAVA guidelines (Washabau et al., 2010), despite being apparently healthy purpose-bred research dogs housed in a controlled environment with no history of vomiting, diarrhea or other signs of GI disease, and despite having normal physical examinations and negative fecal flotations. These findings are similar to previous reports of mild histopathology changes in asymptomatic healthy, control dogs (Junginger et al., 2012, Haas et al., 2014). Histology of the canine GI tract is affected by many factors, including age, intestinal parasites, diet, intestinal flora, medications, and environmental 4-iodo-SAHA (Washabau et al., 2010], Haas et al., 2014). All dogs received monthly topical parasiticide and deworming every 3 months; therefore intestinal parasitism is an unlikely explanation for the mild GI inflammation noted. The authors agree with the observation by Junginger et al., that mild histopathological abnormalities may simply represent background variation in the GI tract of normal dogs (Junginger et al., 2012). We, therefore, believe that, with the possible exception of the dog with mild gastritis, the histologic findings in the dogs in our study are consistent with a healthy GI tract, and that the histamine receptor distribution reported in our study reflects the distribution in clinically normal dogs.
Conclusion
Acknowledgements
The authors would like to thank the Mississippi State University College of Veterinary Medicine (MSU-CVM) histopathology laboratory and immunology laboratory for technical assistance, training, and advice throughout the project. The authors especially would like to thank Stephany Mays for all of her assistance and kindness. This work was supported by the MSU-CVM House Officer Grant.
Introduction
The histamine H3 receptor is one of four histamine receptor subtypes categorised as Family A class of G protein-coupled receptors (GPCRs). Histamine receptors make excellent drug targets, with H1 and H2 receptor antagonists developed for the treatment of allergies and gastroesophageal reflux disorder, respectively. The histamine H3 receptor is primarily expressed in the CNS and is recognised as a pre-synaptic auto-receptor (Arrang et al., 1983) and a hetero-receptor, regulating neurotransmitters such as acetylcholine (Arrang et al., 1995), dopamine (Ellenbroek, 2013), noradrenaline (Schlicker et al., 1990) and serotonin (Threlfell et al., 2004). Furthermore, recent studies have shown that the H3 receptor can modulate both glutamate and GABA transmission (Schlicker and Kathmann, 2017; Nieto-Alamilla et al., 2016). The receptor is widely expressed in human brain with high levels localized to areas associated with cognition, such as the striatum, cerebral cortex, and hippocampus (Pillot et al., 2002). Due to its location and pleiotropic ability to regulate neurotransmission, the H3 receptor has been suggested as a potential drug target for the treatment of Alzheimer's disease, schizophrenia, sleep-wake disorders, neuropathic and osteoarthritic pain, epilepsy, obesity and attention-deficit-hyperactivity disorder. With such a broad range of potential therapeutic indications and the prior successes in developing ligands targeting other histamine receptor subtypes, it was natural that researchers sought to develop H3 receptor selective antagonists.