title: Analgesic effect of dimethyl trisulfide in mice is mediated by TRPA1 and sst4receptors.
abstract: TRPA1 receptors are calcium-permeable ligand-gated channels expressed in primary sensory neurons and involved in inflammation and pain. Activation of these neurons might have analgesic effect. Suggested mechanism of analgesic effect mediated by TRPA1 activation is the release of somatostatin (SOM) and its action on sst4receptors. In the present study analgesic effect of TRPA1 activation on primary sensory neurons by organic trisulfide compound dimethyl trisulfide (DMTS) presumably leading to SOM release was investigated. Opening of TRPA1 by DMTS in CHO cells was examined by patch-clamp and fluorescent Ca2+detection. Ca2+influx upon DMTS administration in trigeminal ganglion (TRG) neurons of TRPA1 receptor wild-type (WT) and knockout (KO) mice was detected by ratiometric Ca2+imaging. SOM release from sensory nerves of murine skin was assessed by radioimmunoassay. Analgesic effect of DMTS in mild heat injury-induced mechanical hyperalgesia was examined by dynamic plantar aesthesiometry. Regulatory role of DMTS on deep body temperature (Tb) was measured by thermocouple thermometry with respirometry and by telemetric thermometry. DMTS produced TRPA1-mediated currents and elevated [Ca2+]iin CHO cells. Similar data were obtained in TRG neurons. DMTS released SOM from murine sensory neurons TRPA1-dependently. DMTS exerted analgesic effect mediated by TRPA1 and sst4receptors. DMTS-evoked hypothermia and hypokinesis were attenuated in freely-moving TRPA1 KO animals. Our study has presented original evidence regarding analgesic action of DMTS which might be due to TRPA1-mediated SOM release from sensory neurons and activation of sst4receptors. DMTS could be a novel analgesic drug candidate.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti utca 12, Pécs, H-7624, Hungary. Electronic address: gabor.pozsgai@aok.pte.hu.
authors.forename: Gábor
authors.initials: G
authors.lastname: Pozsgai
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti utca 12, Pécs, H-7624, Hungary.
authors.forename: Maja
authors.initials: M
authors.lastname: Payrits
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti utca 12, Pécs, H-7624, Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Sághy
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti utca 12, Pécs, H-7624, Hungary.
authors.forename: Réka
authors.initials: R
authors.lastname: Sebestyén-Bátai
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti utca 12, Pécs, H-7624, Hungary.
authors.forename: Elise
authors.initials: E
authors.lastname: Steen
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti utca 12, Pécs, H-7624, Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Szőke
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti utca 12, Pécs, H-7624, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Sándor
authors.affiliation: Institute for Translational Medicine, Medical School, University of Pécs, Szigeti utca 12, Pécs, H-7624, Hungary.
authors.forename: Margit
authors.initials: M
authors.lastname: Solymár
authors.affiliation: Institute for Translational Medicine, Medical School, University of Pécs, Szigeti utca 12, Pécs, H-7624, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Garami
authors.affiliation: Rytmion Ltd., Ősz utca 27, H-6724, Szeged, Hungary; Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Dóm tér 12, H-6720, Szeged, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Orvos
authors.affiliation: Rytmion Ltd., Ősz utca 27, H-6724, Szeged, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Tálosi
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti utca 12, Pécs, H-7624, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Helyes
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti utca 12, Pécs, H-7624, Hungary.
authors.forename: Erika
authors.initials: E
authors.lastname: Pintér
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003412:Cricetulus; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology / Q000627:therapeutic use*; D000074025:TRPA1 Cation Channel / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; D000700:Analgesics; D011687:Purines; D017481:Receptors, Somatostatin; D013440:Sulfides; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; C475685:Trpa1 protein, mouse; C098681:somatostatin receptor subtype-4; C054170:dimethyl trisulfide; D013004:Somatostatin; D002118:Calcium
keywords: Dimethyl trisulfide; Mechanical hyperalgesia; Somatostatin; Spontaneous locomotor activity; TRPA1; sst(4)