title: Prostaglandin D2 Modulates Neuronal Excitation of the Trigeminal Ganglion to Augment Allergic Rhinitis in Guinea Pigs.
abstract: Prostaglandin D2(PGD2) is involved in the pathogenesis of allergic rhinitis. However, the sensory nervous system-mediated contributions of PGD2to the symptoms of allergic rhinitis remain unclear. We investigated the involvement of PGD2in these symptoms and in neuronal excitation by in vivo and ex vivo experiments. In an ovalbumin-induced model of allergic rhinitis in guinea pigs, the number of sneezing, nasal rubbing, and nasal secretion events were assessed after the nasal cavity instillation of PGD2, histamine, or a combination of PGD2and histamine. In situ hybridization for PGD2receptor 1 (DP1) mRNA transcripts and immunohistochemical analysis of histamine H1receptor protein expression in guinea pig trigeminal ganglion (TRG) were performed. The effects of DP1receptor activation on the excitability of TRG neurons to electrical and histamine stimuli were assessed using whole-cell patch-clamp recordings. Histamine induced more sneezing, nasal rubbing, and nasal secretion events than PGD2 PGD2augmented histamine-induced responses, whereas pretreatment with a DP1receptor-selective antagonist completely suppressed PGD2-induced augmentation. DP1receptor mRNA transcripts and H1receptor protein expression could be detected in TRG neurons. Moreover, a DP1receptor agonist caused significant increases in the number of histamine-induced action potentials and depolarization, and reduced the current threshold in small-diameter neurons. Our findings show that PGD2-DP1receptor signaling augments the symptoms of allergic rhinitis via the sensory nervous system by modulating nasal neuronal activation to various stimuli, such as histamine. These findings suggest that DP1receptor antagonist has therapeutic potential for the treatment of allergic rhinitis.
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences (Y.N., H.T., N.I.), Gifu University, and Laboratory of Pharmacology, Department of Bioactive Molecules (H.T., N.I.), Gifu Pharmaceutical University, Gifu, Japan; Discovery Research Laboratory for Innovative Frontier Medicines (Y.N., K.G., S.F., Y.T., M.S.) and Discovery Research Laboratory for Core Therapeutic Areas (M.A.), Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagira
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences (Y.N., H.T., N.I.), Gifu University, and Laboratory of Pharmacology, Department of Bioactive Molecules (H.T., N.I.), Gifu Pharmaceutical University, Gifu, Japan; Discovery Research Laboratory for Innovative Frontier Medicines (Y.N., K.G., S.F., Y.T., M.S.) and Discovery Research Laboratory for Core Therapeutic Areas (M.A.), Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Goto
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences (Y.N., H.T., N.I.), Gifu University, and Laboratory of Pharmacology, Department of Bioactive Molecules (H.T., N.I.), Gifu Pharmaceutical University, Gifu, Japan; Discovery Research Laboratory for Innovative Frontier Medicines (Y.N., K.G., S.F., Y.T., M.S.) and Discovery Research Laboratory for Core Therapeutic Areas (M.A.), Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences (Y.N., H.T., N.I.), Gifu University, and Laboratory of Pharmacology, Department of Bioactive Molecules (H.T., N.I.), Gifu Pharmaceutical University, Gifu, Japan; Discovery Research Laboratory for Innovative Frontier Medicines (Y.N., K.G., S.F., Y.T., M.S.) and Discovery Research Laboratory for Core Therapeutic Areas (M.A.), Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Aoki
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences (Y.N., H.T., N.I.), Gifu University, and Laboratory of Pharmacology, Department of Bioactive Molecules (H.T., N.I.), Gifu Pharmaceutical University, Gifu, Japan; Discovery Research Laboratory for Innovative Frontier Medicines (Y.N., K.G., S.F., Y.T., M.S.) and Discovery Research Laboratory for Core Therapeutic Areas (M.A.), Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Furue
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences (Y.N., H.T., N.I.), Gifu University, and Laboratory of Pharmacology, Department of Bioactive Molecules (H.T., N.I.), Gifu Pharmaceutical University, Gifu, Japan; Discovery Research Laboratory for Innovative Frontier Medicines (Y.N., K.G., S.F., Y.T., M.S.) and Discovery Research Laboratory for Core Therapeutic Areas (M.A.), Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Inagaki
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences (Y.N., H.T., N.I.), Gifu University, and Laboratory of Pharmacology, Department of Bioactive Molecules (H.T., N.I.), Gifu Pharmaceutical University, Gifu, Japan; Discovery Research Laboratory for Innovative Frontier Medicines (Y.N., K.G., S.F., Y.T., M.S.) and Discovery Research Laboratory for Core Therapeutic Areas (M.A.), Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences (Y.N., H.T., N.I.), Gifu University, and Laboratory of Pharmacology, Department of Bioactive Molecules (H.T., N.I.), Gifu Pharmaceutical University, Gifu, Japan; Discovery Research Laboratory for Innovative Frontier Medicines (Y.N., K.G., S.F., Y.T., M.S.) and Discovery Research Laboratory for Core Therapeutic Areas (M.A.), Shionogi & Co., Ltd., Toyonaka, Osaka, Japan michitaka.shichijou@shionogi.co.jp.
authors.forename: Michitaka
authors.initials: M
authors.lastname: Shichijo
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004558:Electric Stimulation; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects*; D010047:Ovalbumin / Q000276:immunology; D018408:Patch-Clamp Techniques; D015230:Prostaglandin D2 / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000187:drug effects; D011982:Receptors, Prostaglandin / Q000187:drug effects; D065631:Rhinitis, Allergic / Q000139:chemically induced* / Q000503:physiopathology / Q000523:psychology; D012912:Sneezing / Q000187:drug effects; D012668:Trigeminal Ganglion / Q000187:drug effects*
chemical_list: D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D006632:Histamine; D010047:Ovalbumin; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor