Behavioural effects of histamine and its antagonists: a review

This review focusses on the behavioural effects of histamine and drugs which affect histaminergic function, particularly the H₁- and H₂-receptors antagonists. Research in this area has assumed considerable importance with increasing interest in the role of brain histamine, the clinical use of both H₁ and H₂ antagonists and evidence of nonmedical use of H₁ antagonists. Results from a number of studies show that H₁ and H₂ antagonists have clear, but distinct subjective effects and that H₁ antagonists have discriminative effects in animals. While H₁ antagonists are reinforcers in certain conditions, histamine itself is a punisher. Moderate doses of H₁ antagonists affect psychomotor performance in some situations, but the results are variable. The exceptions are terfenadine and astemizole, which do not seem to penetrate the blood-brain barrier readily. In studies of schedule-controlled behaviour, marked changes in response rate have been observed following administration of H₁ antagonists, with the magnitude and direction dependent on the dose and the baseline behaviour. Histamine reduces avoidance responding, an effect mediated via H₁-receptors. Changes in drinking and aggressive behaviour have also been observed following histamine administration and distinct roles for H₁- and H₂-receptors have been delineated. Separate H₁- and H₂-receptor mechanisms have also been suggested to account for changes in activity level. While the H₂ antagonists do not always have strong behavioural effects when administered peripherally, there is evidence that cimetidine has a depressant effect on sexual function. These and other findings reveal an important role for histaminergic systems in a wide range of behaviour.     

Functional pharmacology of H1 histamine receptors expressed in mouse preoptic/anterior hypothalamic neurons

BACKGROUND AND PURPOSE

Histamine H₁ receptors are highly expressed in hypothalamic neurons and mediate histaminergic modulation of several brain-controlled physiological functions, such as sleep, feeding and thermoregulation. In spite of the fact that the mouse is used as an experimental model for studying histaminergic signalling, the pharmacological characteristics of mouse H₁ receptors have not been studied. In particular, selective and potent H₁ receptor agonists have not been identified.

EXPERIMENTAL APPROACH

Ca²⁺ imaging using fura-2 fluorescence signals and whole-cell patch-clamp recordings were carried out in mouse preoptic/anterior hypothalamic neurons in culture.

KEY RESULTS

The H₁ receptor antagonists mepyramine and trans-triprolidine potently antagonized the activation by histamine of these receptors with IC₅₀ values of 0.02 and 0.2 μM respectively. All H₁ receptor agonists studied had relatively low potency at the H₁ receptors expressed by these neurons. Methylhistaprodifen and 2-(3-trifluoromethylphenyl)histamine had full-agonist activity with potencies similar to that of histamine. In contrast, 2-pyridylethylamine and betahistine showed only partial agonist activity and lower potency than histamine. The histamine receptor agonist, 6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)heptanecarboxamide (HTMT) had no agonist activity at the H₁ receptors H1 receptors expressed by mouse preoptic/anterior hypothalamic neurons but displayed antagonist activity.

CONCLUSIONS AND IMPLICATIONS

Methylhistaprodifen and 2-(3-trifluoromethylphenyl)histamine were identified as full agonists of mouse H₁ receptors. These results also indicated that histamine H₁ receptors in mice exhibited a pharmacological profile in terms of agonism, significantly different from those of H₁ receptors expressed in other species.     

Histamine H3 receptor antagonists in relation to epilepsy and neurodegeneration: a systemic consideration of recent progress and perspectives

The central histaminergic actions are mediated by H₁, H₂, H₃ and H₄ receptors. The histamine H₃ receptor regulates the release of histamine and a number of other neurotransmitters and thereby plays a role in cognitive and homeostatic processes. Elevated histamine levels suppress seizure activities and appear to confer neuroprotection. The H₃ receptors have a number of enigmatic features like constitutive activity, interspecies variation, distinct ligand binding affinities and differential distribution of prototypic splice variants in the CNS. Furthermore, this Gi/Go-protein-coupled receptor modulates several intracellular signalling pathways whose involvement in epilepsy and neurotoxicity are yet to be ascertained and hence represent an attractive target in the search for new anti-epileptogenic drugs. So far, H₃ receptor antagonists/inverse agonists have garnered a great deal of interest in view of their promising therapeutic properties in various CNS disorders including epilepsy and related neurotoxicity. However, a number of experiments have yielded opposing effects. This article reviews recent works that have provided evidence for diverse mechanisms of antiepileptic and neuroprotective effects that were observed in various experimental models both in vitro and in vivo. The likely reasons for the apparent disparities arising from the literature are also discussed with the aim of establishing a more reliable basis for the future use of H₃ receptor antagonists, thus improving their utility in epilepsy and associated neurotoxicity.     

Psychomotor stimulant effects of the stereoisomers of chlorpheniramine

The behavioral effects of the histamine H₁ antagonistsd- andl-chlorpheniramine and of the H₂ antagonist zolantidine were determined in squirrel monkeys responding under a fixed-interval (FI) 3-min schedule of stimulus-shock termination. Althoughd-chlorpheniramine is known to be much more potent thanl-chlorpheniramine for antagonizing H₁ receptor-mediated effects of histamine or displacing [³H]-mepyramine from histamine H₁ receptors, similar doses of racemic chlorpheniramine and thed- andl-isomers (3.0–10.0 mg/kg) produced comparable increases in rates of responding. Zolantidine (1.0–17.0 mg/kg) did not alter or, at the highest dose, markedly decreased responding. These findings suggest that the psychomotor stimulant effects of chlorpheniramine involve actions other than the blockade of histamine H₁ or H₂ receptors. Selected H₁ antagonists and cocaine are known to have comparable rateincreasing, reinforcing, and discriminative stimulus effects and, recently, the enantiomers of chlorpheniramine have been shown to displace [³H]-cocaine from binding sites in CNS with approximately equal potency. Possibly, such actions mediate behavioral effects common to H₁ antagonists and cocaine.     

JNJ-10181457, a selective non-imidazole histamine H3 receptor antagonist, normalizes acetylcholine neurotransmission and has efficacy in translational rat models of cognition

Histamine 3 (H₃) receptors are distributed throughout the brain and regulate histamine as well as the activity of other neurotransmitters including acetylcholine (ACh). Impaired ACh neurotransmission is associated with deficits of cognitive-related functioning in many species including humans. The goal of these studies was to evaluate the behavioral and neurochemical effects of JNJ-10181457, a selective non-imidazole histamine H₃ receptor antagonist, in rats. The pharmacokinetic profile and receptor occupancy of JNJ-10181457 were tested. The efficacy of JNJ-10181457 was evaluated, acutely, in the imetit-induced water licking model, delayed non-matching to position (DNMTP) task and microdialysis studies. In addition, the effects of repeated administration of JNJ-10181457 were evaluated in the reversal learning task. A single administration of JNJ-10181457 (10 mg/kg, i.p.) resulted in significant plasma and brain exposure and maximal H₃ receptor occupancy. In addition, JNJ-10181457 reversed imetit-induced water licking, similarly to thioperamide (10 mg/kg, i.p.). In the DNMTP task, scopolamine (0.06 mg/kg, i.p.) significantly decreased percentage correct responding. These effects were significantly reversed by JNJ-10181457 (10 mg/kg, i.p.) and also by donepezil (1 mg/kg, i.p.), an acetylcholinesterase inhibitor, and were associated with normalization of ACh neurotransmission in the cortex. Repeated administration of JNJ-10181457 (10 mg/kg, i.p.) significantly increased percentage correct responding in the reversal learning task. Treatment discontinuation was not associated with rebound effects on cognition. These results indicate that selective blockade of histamine H₃ receptors might have therapeutic utility for the treatment of working memory deficits and learning disorders, especially those in which ACh neurotransmission is compromised.     

Regulation of sterol synthesis by histamine in human mononuclear leukocytes: Roles of H1- and H2-receptors

Summary The effect of histamine on sterol synthesis has been investigated in freshly isolated human mononuclear leukocytes from healthy subjects.Incubation of cells for 6 h in a medium containing lipid depleted serum led to a threefold increase in the incorporation of (¹⁴C)-acetate or tritiated water into sterols. Histamine 0.3 µM added to the incubation medium at zero time inhibited this induction by 35% with a sigmoidal log dose-effect curve.The receptors mediating this action were characterised pharmacologically by using selective H₁- and H₂-agonists and -antagonists. The H₂-agonists impromidine and 4-methylhistamine mimicked the effect of histamine on sterol synthesis, the suppression being 42% and 31%, respectively, at a concentration of 1 µM. In contrast, the H₁-agonist 2-pyridylethylamine did not affect the pathway. The H₂-antagonist cimetidine (10 µM) but not the H₁-antagonist mepyramine (10 µM) totally reversed the inhibition of sterol synthesis by histamine.The results provide evidence that sterol synthesis in human mononuclear leukocytes is regulated by histamine, which appears to act predominantly via H₂-receptors.     

Histamine H1- and H2-receptors in the gastrointestinal circulation

Summary Evidence for the presence of specific histamine H₁- and H₂-receptors in the gastrointestinal circulation was obtained using histamine, 2-methylhistamine (a specific H₁-agonist), 4-methylhistamine (a specific H₂-agonist), and selective H₁- and H₂-receptor antagonists in the anesthetized dog. Histamine and 2-methylhistamine increased conductance in the vascular beds of the superior mesenteric artery, the left gastric artery and the common hepatic artery, whereas 4-methylhistamine mainly enhanced conductance in the vascular beds of the left gastric artery and the common hepatic artery. All three agents depressed systemic arterial blood pressure. The vasodilatory effect of histamine and 2-methylhistamine on the superior mesenteric artery bed occurred earlier and was of shorter duration than their effect on the two other vessels. The H₁-receptor antagonists mepyramine and clemastine blocked the response of the superior mesenteric artery bed to histamine, but had a lesser inhibitory effect on the histamine response of the common hepatic artery and the left gastric artery. The addition of the H₂-receptor antagonist cimetidine to mepyramine blockade augmented the inhibiting effect of mepyramine on the common hepatic artery. Cimetidine bolus injections prevented enhancement of vascular conductance by 4-methylhistamine, but did not influence conductance enhancement by histamine or 2-methylhistamine. These data demonstrate there are separable histamine H₁- and H₂-receptors in the gastrointestinal circulation which are distinguished by anatomic location, temporal relationships of receptor response, and response to specific histamine H₁- and H₂-agonists and antagonists.     

Characterization of histamine H2-receptors in human neutrophils with a series of guanidine analogues of impromidine

Summary Human neutrophils possess an NADPH oxidase which catalyzes superoxide (O _inf2 ^sup– ) formation and is activated by chemotactic peptides. Histamine inhibits O _inf2 ^sup–1 formation via H₂-receptors (Burde et al. 1989). We characterized the neutrophil H₂-receptor with a series of new guanidine-type H₂-agonists structurally derived from impromidine. Histamine inhibited O _inf2 ^sup– formation with an IC₅₀ value of 6.7 ± 1.2 M. Five aryloxy- and arylthioalkylguanidines were less potent and effective than histamine. Several arpromidine-like phenyl(pyridylalkyl)guanidines were either full or partial H₂-agonists. Some guanidines possess a three-membered carbon chain connecting the aromatic rings and the guanidine group; they were similarly potent and effective as histamine. Shortening or elongation of the carbon chain substantially decreased the potency and intrinsic activity of the guanidines. Halogenation of the phenyl ring did not substantially affect the potency and intrinsic activity of the compounds in comparison to the non-substituted parent compound. The H₂-antagonist, famotidine, competitively antagonized inhibition of O _inf2 ^sup– formation caused by the guanidine, arpromidine, with a pA₂ value of 6.84. The H₂-antagonist, cimetidine, differentially counteracted inhibition caused by partial and full H₂-agonists. Partial H₂-agonists antagonized the effects of histamine. The inhibitor of phosphodiesterases, 3-isobutyl-lmethylxanthine, additively enhanced the inhibitory effects of histamine and guanidines. The properties of the neutrophil H₂-receptor were compared with literature data concerning properties of the H₂-receptor of the guinea pig atrium. In the latter system, guanidines are full H₂-agonists with potencies of up to 125-fold of that of histamine. Our data indicate that guanidines inhibit O _inf2 ^sup– formation in human neutrophils via H₂-receptors. The structure/activity relationship for the neutrophil H₂-receptor substantially differs from the one for the H₂-receptor in the guinea pig atrium, suggesting that the neutrophil H₂-receptor has cell type-specific properties. Other possibilities to explain the differences between H₂-receptors in these systems are discussed. Send offprint requests to R. Seifert at the above address     

Histamine analogs. 27. Bis(2,2'-histamine)

Histamine Analogues, XXVII: Bis(2,2′-histamines) p-Phenylenebis(2,2′-histamine) ( 6a ), ethylenebis(2,2′-histamine) ( 6b ), tetramethylenebis(2,2′-histamine) ( 6c ), and hexamethylenebis(2,2′-histamine) ( 6d ) were prepared and tested for histamine H₁,-and H₂-agonistic activity.     

The new potent and selective histamine H2 receptor agonist amthamine as a tool to study gastric secretion

Summary The new histamine H₂ receptor agonist amthamine, [2-amino-5-(2-aminoethyl)-4-methylthiazole], was tested for its activity on gastric acid secretion in different in vivo and in vitro experimental models. Amthamine induced a dose-related increase in acid secretion both in conscious cats with a gastric fistula (ED₅₀ = 0.069 mol/kg/h) and in anaesthetized rats with a lumen-perfused stomach (ED₅₀ = 11.69 gmol/kg i.v.). In this last preparation the efficacy of amthamine was significantly higher than that of histamine and dimaprit. Amthamine was an effective secretagogue also in the rat isolated gastric fundus, behaving as a full agonist (EC₅₀ = 18.9 mol/l). In all the experimental models amthamine was more potent than dimaprit (from 3 to 10 fold) and approximately equipotent with histamine, and its effect was competitively antagonized by the histamine H₂ receptor antagonists famotidine or ranitidine. Experiments with H₁ and H₃ receptor antagonists indicated that Amhamine is devoid of stimulatory activity at H₁ and H₃ receptors. The present data indicate that amthamine is a full agonist at histamine H₂ receptors and, being more effective and selective than the other compounds of the family, it may represent a good alternative to the other available histamine H₂ receptor agonists for the study of gastric acid secretion.Correspondence to G. Bertaccini at the above address     

Ca2+ signals evoked by histamine H1 receptors are attenuated by activation of prostaglandin EP2 and EP4 receptors in human aortic smooth muscle cells

Background and Purpose

Histamine and prostaglandin E₂ (PGE₂), directly and via their effects on other cells, regulate the behaviour of vascular smooth muscle (VSM), but their effects on human VSM are incompletely resolved.

Experimental Approach

The effects of PGE₂ on histamine-evoked changes in intracellular free Ca²⁺ concentration ([Ca²⁺]_i) and adenylyl cyclase activity were measured in populations of cultured human aortic smooth muscle cells (ASMCs). Selective ligands of histamine and EP receptors were used to identify the receptors that mediate the responses.

Key Results

Histamine, via H₁ receptors, stimulates an increase in [Ca²⁺]_i that is entirely mediated by activation of inositol 1,4,5-trisphosphate receptors. Selective stimulation of EP₂ or EP₄ receptors attenuates histamine-evoked Ca²⁺ signals, but the effects of PGE₂ on both Ca²⁺ signals and AC activity are largely mediated by EP₂ receptors.

Conclusions and Implications

Two important inflammatory mediators, histamine via H₁ receptors and PGE₂ acting largely via EP₂ receptors, exert opposing effects on [Ca²⁺]_i in human ASMCs.     

Effect of some new histamine H2-receptor antagonists on the guinea-pig papillary muscle

Summary Several histamine H₂-receptor antagonists (cimetidine, ranitidine, oxmetidine and tiotidine) were tested for their activity on the papillary muscle of the guinea pig stimulated by histamine. All of the compounds exerted a competitive antagonism against histamine the order of potency being tiotidine > oxmetidine > ranitidine > cimetidine. Oxmetidine was the only drug which at high concentrations (10^–6 M) decreased the maximum response of histamine probably because of non specific effects of the molecule already described in the literature. As it was expected, the H₁-receptor antagonist, mepyramine, exerted a non-competitive antagonism.     

Effects of activation of central nervous histamine receptors in cardiovascular regulation; studies in H<Subscript>1</Subscript> and H<Subscript>2</Subscript> receptor gene knockout mice

To elucidate the central roles of histamine receptors in cardiovascular regulatory system, systolic, mean, and diastolic blood pressures (BPs) and heart rate (HR) were examined in conscious H₁ receptor gene knockout (H₁KO) mice, H₂ receptor gene knockout (H₂KO) mice, H₁ and H₂ receptor gene double knockout (DKO) mice, and their respective control mice by the tail-cuff system. Histamine, histamine-trifluoromethyl-toluidine derivative (HTMT, an H₁ agonist), dimaprit (an H₂ agonist), and immepip (an H₃ agonist) were intrathecally administered to these KO mice and control mice. Basal BPs and HR were not different among these three KO mice and their control or wild-type mice. Intrathecal administration of histamine significantly increased BPs and decreased HR in control mice. The increases in BPs were produced by histamine in H₁KO and H₂KO mice and by HTMT and dimaprit in C57BL mice. The pressor responses by HTMT and dimaprit in C57BL mice were greater than those by histamine in H₁KO and H₂KO mice, although the same decreases in HR were induced by histamine in C57BL and H₁KO mice and by dimaprit in C57BL mice. The selective stimulation of H₃ receptors by immepip produced a consistent decrease in BPs in control mice. These results obtained with the exogenous selective agonists of three histamine receptors suggest that the pressor responses to histamine are mediated through the stimulation of both H₁ and H₂ receptors, whereas the atropine-sensitive decrease in heart rate is mainly due to H₂ receptors which activate the vagal output to the heart.     

Pharmacological characterization of the new histamine H4 receptor agonist VUF 8430

Background and purpose:

We compare the pharmacological profiles of a new histamine H₄ receptor agonist 2-(2-guanidinoethyl)isothiourea (VUF 8430) with that of a previously described H₄ receptor agonist, 4-methylhistamine.

Experimental approach:

Radioligand binding and functional assays were performed using histamine H₄ receptors expressed in mammalian cell lines. Compounds were also evaluated ex vivo in monocyte-derived dendritic cells endogenously expressing H₄ receptors and in vivo in anaesthetized rats for gastric acid secretion activity.

Key results:

Both VUF 8430 and 4-methylhistamine were full agonists at human H₄ receptors with lower affinity at rat and mouse H₄ receptors. Both compounds induced chemotaxis of monocyte-derived dendritic cells. VUF 8430 also showed reasonable affinity and was a full agonist at the H₃ receptor. Agmatine is a metabolite of arginine, structurally related to VUF 8430, and was a H₄ receptor agonist with micromolar affinity. At histamine H₃ receptors, agmatine was a full agonist, whereas 4-methylhistamine was an agonist only at high concentrations. Both VUF 8430 and agmatine were inactive at H₁ and H₂ receptors, whereas 4-methylhistamine is as active as histamine at H₂ receptors. In vivo, VUF 8430 only caused a weak secretion of gastric acid mediated by H₂ receptors, whereas 4-methylhistamine, dimaprit, histamine and amthamine, at equimolar doses, induced 2.5- to 6-fold higher output than VUF 8430.

Conclusions and implications:

Our results suggest complementary use of 4-methylhistamine and VUF 8430 as H₄ receptor agonists. Along with H₄ receptor antagonists, both agonists can serve as useful pharmacological tools in studies of histamine H₄ receptors.     

Human gastric mucosal adenylate cyclase: Activation by histamine-H2-receptor stimulation and inhibition by cimetidine in vitro and in peptic ulcer patients

Summary Biopsy specimens of human fundic mucosa from 96 subjects were assayed for adenylate cyclase activity to characterize specificity of the histamine receptor with selective agonists and antagonists in vitro, and to study the effect of cimetidine therapy. Histamine and the selective histamine H₂-receptor agonist dimaprit were almost equally potent throughout the concentration-response curve (10^–7–10^–3 mol/l); maximal stimulation was obtained with concentrations of 10^–4–10^–3 mol/l, and half maximal stimulation with about 10^–5 mol/l. The selective H₁-receptor agonist PEA 10^–5 and 10^–3 mol/l failed to stimulate adenylate cyclase. Mepyramine 10^–6 mol/l, a selective H₁-receptor antagonist, and cimetidine 10^–6 mol/l, a selective H₂-receptor antagonist, did not affect basal adenylate cyclase activity. Histamine-stimulated adenylate cyclase was inhibited in a concentration dependent manner by cimetidine 10^–7 and 10^–5 mol/l, but not by the same concentrations of mepyramine. Almost identical basal adenylate cyclase activities of about 150 pmol cAMP/mg protein/20 min were found in gastric mucosal biopsies from controls and from peptic ulcer patients, whether or not treated with cimetidine. Histamine 10^–5 mol/l doubled adenylate cyclase activity in the controls and the untreated ulcer group, but was completely ineffective in specimens from the cimetidine-treated peptic ulcer patients. The data underline the concept that the effects of histamine on acid secretion and on adenylate cyclase activity are linked together and that the therapeutic effect of cimetidine in ulcer treatment is related to histamine H₂-receptor blockade followed by inhibition of adenylate cyclase.     

Evidence that clonidine can activate histamine h2-receptors in rat cerebral cortex

Iontophoretically applied clonidine, histamine and noradrenaline reduced the discharge rate of cerebral cortical neurones in rats anaesthetized with a mixture of methoxyflurane, nitrous oxide and oxygen. Metiamide, an H₂-histamine receptor antagonist, reversibly antagonized the depressant effects of clonidine and histamine but not of noradrenaline. These results indicate that clonidine cat activate histamine H₂-receptors on central neurones.     

Cyclopropyl methanone derivatives,their preparation and their therapeutic use

Interest in the development of novel histamine H₃ antagonists, especially for the treatment of obesity and CNS disorders, remains strong, as evidenced by recent patent activity from a large number of pharmaceutical companies. The present application from Sanofi-Aventis discloses a series of cyclopropyl methanone derivatives that display high receptor binding affinity and selectivity for the H₃ receptor together with an ability to reduce food intake in rat.     

Temporal responses of cutaneous blood flow and plasma catecholamine concentrations to histamine H1- or H2-receptor stimulation in man

Summary We have studied the effect of histamine and H₁- or H₂-receptor antagonists on cutaneous blood flow and catecholamine release in man.Histamine was infused alone or in combination with mepyramine, an H₁-antagonist or cimetidine, an H₂-antagonist for 2 h. Cutaneous blood flow was measured continously with a laser Doppler flowmeter, and noradrenaline and adrenaline concentrations were determined in blood samples drawn every 15 min.The infusion of histamine caused an immediate and sustained vasodilatation. The Concomitant infusion of mepyramine prevented the immediate vasodilatation, but had no effect on the sustained response. The Concomitant infusion of cimetidine was without effect on the immediate vasodilatation, but abolished the sustained response. Infusion of the antagonists alone had no effect on cutaneous blood flow.Histamine caused a rapid and sustained increase in plasma noradrenaline, while the increase during concomitant H₁-receptor blockade was delayed but achieved the level observed during the histamine infusion. The response to histamine during H₂-receptor blockade was small and transient. The rise in plasma adrenaline was not significant.These findings suggest that histamine causes an immediate cutaneous vasodilatation through H₁-receptors and a more sustained response through H₂-receptors. The vasodilatation is accompanied by an increase in plasma catecholamine concentrations. Despite the continuous infusion of histamine, blood flow decreased during the last hour of histamine infusion, while the plasma noradrenaline concentration was still elevated.     

The role of histamine H4 receptor in immune and inflammatory disorders

Since its discovery at the beginning of the 20th century, histamine has been established to play a pathophysiological regulatory role in cellular events through binding to four types of G-protein-coupled histamine receptors that are differentially expressed in various cell types. The discovery, at the turn of the millennium, that the histamine H₄ receptor is largely expressed in haemopoietic cells as well as its chemotactic properties designate its regulatory role in the immune system. H₄ receptors modulate eosinophil migration and selective recruitment of mast cells leading to amplification of histamine-mediated immune responses and eventually to chronic inflammation. H₄ receptor involvement in dendritic cell activation and T cell differentiation documents its immunomodulatory function. The characterization of the H₄ as the immune system histamine receptor directed growing attention towards its therapeutic exploitation in inflammatory disorders, such as allergy, asthma, chronic pruritus and autoimmune diseases. The efficacy of a number of H₄ receptor ligands has been evaluated in in vivo and in vitro animal models of disease and in human biological samples. However, before reaching decisive conclusions on H₄ receptor pathophysiological functions and therapeutic exploitation, identification of genetic polymorphisms and interspecies differences in its relative actions and pharmacological profile need to be addressed and taken into consideration. Despite certain variations in the reported findings, the available data strongly point to the H₄ receptor as a novel target for the pharmacological modulation of histamine-transferred immune signals and offer an optimistic perspective for the therapeutic exploitation of this promising new drug target in inflammatory disorders.