title: Histamine potentiates acid-induced responses mediating transient receptor potential V1 in mouse primary sensory neurons.
abstract: In inflamed tissues, extracellular pH decreases and acidosis is an important source of pain. Histamine is released from mast cells under inflammatory conditions and evokes the pain sensation in vivo, but the cellular mechanism of histamine-induced pain has not been well understood. In the present study, we examined the effects of histamine on [Ca(2+)](i) and membrane potential responses to acid in isolated mouse dorsal root ganglion (DRG) neurons. In capsaicin-sensitive DRG neurons from wild-type mice, acid (>pH 5.0) evoked [Ca(2+)](i) increases, but not in DRG neurons from transient receptor potential V1 (TRPV1) (-/-) mice. Regardless of isolectin GS-IB4 (IB4)-staining, histamine potentiated [Ca(2+)](i) responses to acid (>or=pH 6.0) that were mediated by TRPV1 activation. Histamine increased membrane depolarization induced by acid and evoked spike discharges. RT-PCR indicated the expression of all four histamine receptors (H1R, H2R, H3R, H4R) in mouse DRG. The potentiating effect of histamine was mimicked by an H1R agonist, but not H2R-H4R agonists and was inhibited only by an H1R antagonist. Histamine failed to potentiate the [Ca(2+)](i) response to acid in the presence of inhibitors for phospholipase C (PLC) and protein kinase C (PKC). A lipoxygenase inhibitor and protein kinase A inhibitor did not affect the potentiating effects of histamine. Carrageenan and complete Freund's adjuvant produced inflammatory hyperalgesia, but these inflammatory conditions did not change the potentiating effects of histamine in DRG neurons. The present results suggest that histamine sensitizes acid-induced responses through TRPV1 activation via H1R coupled with PLC/PKC pathways, the action of which may be involved in the generation of inflammatory pain.
authors.affiliation: Laboratory of Pharmacology, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kajihara
authors.forename: M
authors.initials: M
authors.lastname: Murakami
authors.forename: T
authors.initials: T
authors.lastname: Imagawa
authors.forename: K
authors.initials: K
authors.lastname: Otsuguro
authors.forename: S
authors.initials: S
authors.lastname: Ito
authors.forename: T
authors.initials: T
authors.lastname: Ohta
mesh_terms: D000143:Acids / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism*; D006632:Histamine / Q000378:metabolism / Q000494:pharmacology*; D017442:Histamine Agonists / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D018836:Inflammation Mediators / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009619:Nociceptors / Q000378:metabolism*; D010146:Pain / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000187:drug effects* / Q000235:genetics; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000143:Acids; D004791:Enzyme Inhibitors; D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D018836:Inflammation Mediators; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D006632:Histamine; D011493:Protein Kinase C; D010738:Type C Phospholipases