title: Pleiotropic effect of histamine H4 receptor modulation in the central nervous system.
abstract: The histamine H4 receptor (H4R) is expressed primarily on cells involved in inflammation and immune responses. Recently, it has been reported the functional expression of H4R within neurons of the central nervous system, but their role has been poorly understood. The present study aimed to elucidate the physiopathological role of cerebral H4R in animal models by the intracerebroventricular administration of the H4R agonist VUF 8430 (20-40 μg per mouse). Selectivity of results was confirmed by the prevention of the effects produced by the H4R antagonist JNJ 10191584 (3-9 mg/kg p.o.). Neuronal H4R activation induced acute thermal antinociception, indicating that neuronal histamine H4R might be involved in the production of antinociception in the absence of an inflammatory process. An anxiolytic-like effect of intensity comparable to that exerted by diazepam, used as reference drug, was produced in the light-dark box test. VUF 8430 reversed the scopolamine-induced amnesia in the passive avoidance test and showed anorexant activity in food deprived mice. Conversely, the H4R activation did not modify the immobility time in the tail suspension test. Rotarod performance test was employed to demonstrate that the effects observed following the administration of VUF 8430 and JNJ 10191584 were not due to impaired motor function of animals. Furthermore, both compounds did not alter spontaneous mobility and exploratory activity in the hole board test. These results show the antinociceptive, antiamnesic, anxiolytic and anorexant effects induced by neuronal H4R agonism, suggesting that H4 modulators may have broader utility further the control of inflammatory and immune processes.
authors.affiliation: Department of Preclinical and Clinical Pharmacology, University of Florence, Viale G. Pieraccini 6, I-50139 Florence, Italy. nicoletta.galeotti@unifi.it
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Galeotti
authors.forename: Maria Domenica
authors.initials: MD
authors.lastname: Sanna
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
mesh_terms: D000700:Analgesics / Q000819:agonists / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000819:agonists / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000627:therapeutic use; D001067:Appetite Depressants / Q000737:chemistry / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology; D017442:Histamine Agonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018697:Nootropic Agents / Q000819:agonists / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D011897:Random Allocation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000700:Analgesics; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D001067:Appetite Depressants; D001562:Benzimidazoles; D006146:Guanidines; D017442:Histamine Agonists; D006633:Histamine Antagonists; C498829:Hrh4 protein, mouse; C506811:JNJ 10191584; D009419:Nerve Tissue Proteins; D018697:Nootropic Agents; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C516215:S-(2-guanidylethyl)isothiourea; D013890:Thiourea