title: Capsaicin-sensitive sensory nerves exert complex regulatory functions in the serum-transfer mouse model of autoimmune arthritis.
abstract: OBJECTIVE
  The K/BxN serum-transfer arthritis is a widely-used translational mouse model of rheumatoid arthritis, in which the immunological components have thoroughly been investigated. In contrast, little is known about the role of sensory neural factors and the complexity of neuro-immune interactions. Therefore, we analyzed the involvement of capsaicin-sensitive peptidergic sensory nerves in autoantibody-induced arthritis with integrative methodology.
  
  
  METHODS
  Arthritogenic K/BxN or control serum was injected to non-pretreated mice or resiniferatoxin (RTX)-pretreated animals where capsaicin-sensitive nerves were inactivated. Edema, touch sensitivity, noxious heat threshold, joint function, body weight and clinical arthritis severity scores were determined repeatedly throughout two weeks. Micro-CT and in vivo optical imaging to determine matrix-metalloproteinase (MMP) and neutrophil-derived myeloperoxidase (MPO) activities, semiquantitative histopathological scoring and radioimmunoassay to measure somatostatin in the joint homogenates were also performed.
  
  
  RESULTS
  In RTX-pretreated mice, the autoantibody-induced joint swelling, arthritis severity score, MMP and MPO activities, as well as histopathological alterations were significantly greater compared to non-pretreated animals. Self-control quantification of the bone mass revealed decreased values in intact female mice, but significantly greater arthritis-induced pathological bone formation after RTX-pretreatment. In contrast, mechanical hyperalgesia from day 10 was smaller after inactivating capsaicin-sensitive afferents. Although thermal hyperalgesia did not develop, noxious heat threshold was significantly higher following RTX pretreatment. Somatostatin-like immunoreactivity elevated in the tibiotarsal joints in non-pretreated, which was significantly less in RTX-pretreated mice.
  
  
  CONCLUSIONS
  Although capsaicin-sensitive sensory nerves mediate mechanical hyperalgesia in the later phase of autoantibody-induced chronic arthritis, they play important anti-inflammatory roles at least partially through somatostatin release.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Pécs, Hungary; János Szentágothai Research Centre, Molecular Pharmacology Research Team, University of Pécs, Pécs, Hungary; Centre for Neuroscience, University of Pécs, Medical School, Pécs, Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Borbély
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Pécs, Hungary; János Szentágothai Research Centre, Molecular Pharmacology Research Team, University of Pécs, Pécs, Hungary; Centre for Neuroscience, University of Pécs, Medical School, Pécs, Hungary.
authors.forename: Bálint
authors.initials: B
authors.lastname: Botz
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Pécs, Hungary; János Szentágothai Research Centre, Molecular Pharmacology Research Team, University of Pécs, Pécs, Hungary; Centre for Neuroscience, University of Pécs, Medical School, Pécs, Hungary.
authors.forename: Kata
authors.initials: K
authors.lastname: Bölcskei
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Pécs, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Kenyér
authors.affiliation: Department of Pathology, University of Pécs, Medical School, Pécs, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Kereskai
authors.affiliation: János Szentágothai Research Centre, Molecular Pharmacology Research Team, University of Pécs, Pécs, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Kiss
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Pécs, Hungary; János Szentágothai Research Centre, Molecular Pharmacology Research Team, University of Pécs, Pécs, Hungary; Centre for Neuroscience, University of Pécs, Medical School, Pécs, Hungary; PharmInVivo Ltd, Pécs, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Szolcsányi
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Pécs, Hungary; János Szentágothai Research Centre, Molecular Pharmacology Research Team, University of Pécs, Pécs, Hungary; Centre for Neuroscience, University of Pécs, Medical School, Pécs, Hungary; PharmInVivo Ltd, Pécs, Hungary.
authors.forename: Erika
authors.initials: E
authors.lastname: Pintér
authors.affiliation: Department of Physiology, and MTA-SE "Lendület" Inflammation Physiology Research Group, Semmelweis University, School of Medicine, Budapest, Hungary.
authors.forename: Janka Zsófia
authors.initials: JZ
authors.lastname: Csepregi
authors.affiliation: Department of Physiology, and MTA-SE "Lendület" Inflammation Physiology Research Group, Semmelweis University, School of Medicine, Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Mócsai
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Pécs, Hungary; János Szentágothai Research Centre, Molecular Pharmacology Research Team, University of Pécs, Pécs, Hungary; Centre for Neuroscience, University of Pécs, Medical School, Pécs, Hungary; PharmInVivo Ltd, Pécs, Hungary; MTA-PTE NAP B Pain Research Group, Hungary. Electronic address: zsuzsanna.helyes@aok.pte.hu.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Helyes
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental; D001172:Arthritis, Rheumatoid; D002211:Capsaicin / Q000494:pharmacology; D004195:Disease Models, Animal; D004224:Diterpenes / Q000494:pharmacology*; D004487:Edema; D006614:Hindlimb; D006930:Hyperalgesia; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009619:Nociceptors / Q000187:drug effects* / Q000502:physiology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D017382:Reactive Oxygen Species; D018689:Sensory System Agents / Q000494:pharmacology; D013004:Somatostatin / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists; D013643:Tarsus, Animal / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D055114:X-Ray Microtomography
chemical_list: D004224:Diterpenes; D017382:Reactive Oxygen Species; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D013004:Somatostatin; C024353:resiniferatoxin; D009195:Peroxidase; D020782:Matrix Metalloproteinases; D002211:Capsaicin
keywords: Capsaicin-sensitive sensory nerves; Inflammation; Matrix-metalloproteinase; Pain; Somatostatin