Peripheral Actions and Therapeutic Potential in Periphery

Histamine H₃ Receptors Are Involved in the Protective Effect of Ghrelin against HCl-Induced Gastric Damage in Rats

“…In particular, the involvement of H 3 Rs was ruled out based on the ineffectiveness of the H 3 R antagonist clobenpropit. As opposed to the study by Konturek et al [30] , our data clearly suggest that histamine released by ghrelin activates H 3 Rs to afford protective effects, in accordance with literature data [31][32][33][34] . The reason for this discrepancy may possibly be attributed to the use of clobenpropit; indeed, it has recently been demonstrated that this compound, originally described as a potent and highly selective H 3 R antagonist [35] , also displays affinity for the newly discovered H 4 R, behaving as a partial agonist in functional assays [36] .…”

“…In parallel experiments, the selective H 3 R agonist, immethridine (30 mg/kg s.c.) was tested against 0.6 N HCl-induced gastric damage in the absence or in the presence of UCL2138 or the ghrelin receptor antagonist, [ D -Lys 3 ]-GHRP-6 (100 g/kg i.p.). The dose of immethridine was chosen on the basis of previous experiments [31] as the dose inducing the maximum protective effects against 0.6 N HCl. Stomachs were evaluated for the presence of macroscopic gastric lesions according to the method above described.…”

“…The involvement of histamine in the acid secretory and protective effects of ghrelin is a matter of debate: an increase in histidine decarboxylase expression in the rat gastric mucosa after peripheral administration of ghrelin was not unanimously detected [16,27,30] ; moreover, the study by Konturek et al [30] ruled out a role for histamine H 3 receptors (H 3 Rs) in the action of ghrelin, as the H 3 R antagonist clobenpropit did not modify ghrelin-induced gastroprotection. This was rather unexpected since previously published data have clearly shown that the histamine H 3 R subtype is predominantly involved in gastric mucosal protection [31][32][33][34] . The use of clobenpropit is questionable since this compound, originally described as a highly selective H 3 R antagonist [35] , displays affinity for histamine H 4 receptors (H 4 Rs) [36] ; as this last receptor has been recently involved in ulcerogenesis [37] , further studies employing more selective H 3 R ligands are required in order to identify the histamine receptor subtype involved in the gastric effects of ghrelin.…”

Role of histamine H4 receptors in the gastrointestinal tract

“…The major role of histamine and of H 2 Rs in the stomach is the regulation of acid secretion by the parietal (39,40,43,55); however, functional data were dependent on the species and the experimental assay (40,44,46). The negative regulation of histamine release from ECL cells has been proposed by several authors as the main function mediated by H 3 Rs in the rat stomach (33,43).…”

“…In the recent years, it has become apparent that intestinal mast cell mediators and enteric nervous system are key players in the intricate neuroimmune network, that regulates intestinal homeostasis and the inflammatory response to noxious stimuli (90). Histamine can influence neurotransmission at both submucous and myenteric plexus, thereby modifying intestinal secretion and motility, through the activation of the three receptors H 1 , H 2 and H 3 (32,39,45,46,(91)(92)(93). The occurrence of a new receptor subtype in the intestine was firstly hypothesized by Schworer et al (94), who identified in the porcine small intestine an H 3 -like receptor Figure 2.…”