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Neurogenic components of trypsin- and thrombin-induced inflammation in rat skin, in vivo

Authors

  • Otilia Obreja,

    1. Department of Anaesthesiology and Intensive Care, Faculty of Clinical Medicine Mannheim, University of Medicine Heidelberg, Mannheim, Germany;
    2. Department of Physiology, University of Medicine Erlangen, Erlangen, Germany;
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  • Roman Rukwied,

    1. Department of Anaesthesiology and Intensive Care, Faculty of Clinical Medicine Mannheim, University of Medicine Heidelberg, Mannheim, Germany;
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  • Martin Steinhoff,

    1. Department of Dermatology, University of Muenster, Muenster, Germany
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  • Martin Schmelz

    Corresponding author
    1. Department of Anaesthesiology and Intensive Care, Faculty of Clinical Medicine Mannheim, University of Medicine Heidelberg, Mannheim, Germany;
    2. Department of Physiology, University of Medicine Erlangen, Erlangen, Germany;
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Professor Dr med. Martin Schmelz
Department of Anaesthesiology and Intensive Care
Faculty of Clinical Medicine Mannheim
Ruprecht-Karls-University Heidelberg
Theodor-Kutzer-Ufer 1-3
68167 Mannheim
Germany
Tel.: +49 621 383 5015/3767
Fax: +49 621 383 1463
e-mail: martin.schmelz@anaes.ma.uni-heidelberg.de

Abstract

Abstract:  Activation of protease-activated receptors (PAR) can induce vasodilation (VD) and increase of vascular permeability either directly by stimulating endothelial cells or indirectly via activation of nociceptors and subsequent release of neuropeptides (neurogenic inflammation). We aimed to estimate the relative contribution of the two pathways for stimulation with endogenous activators of PAR-2 (trypsin) and of PAR-1, 3 and 4 (thrombin) using in vivo dermal microdialysis in rats. Protein extravasation (PE) was assessed by increase of protein concentration in the dialysate, and VD was quantified by laser Doppler scanning. Both trypsin (10−8−10−4 M) and thrombin (10−6, 10−5.5 and 10−5 M) provoked PE and local VD in a dose-dependent manner. Trypsin (10−4 M)-induced PE was inhibited by 87.2 ± 21% due to the substance P (SP) NK1 receptor antagonist SR140333. VD was blocked by 58.15 ± 10.1% in response to the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP8-37. By contrast, CGRP8-37 did not affect thrombin-induced VD, while blockade of SP receptors prevented the PE elicited only by low doses of thrombin (10−6 M), being ineffective at higher thrombin concentrations. In conclusion, intradermal trypsin elicits a neurogenic inflammation in rat, probably mediated via PAR-2 activation on nociceptors and subsequent SP and CGRP release. Thrombin-induced PE and VD are mediated mainly by a non-neurogenic mechanism.

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