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Role of capsaicin-sensitive nerves and tachykinins in mast cell tryptase-induced inflammation of murine knees

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Abstract

Objective, design

Mast cell tryptase (MCT) is elevated in arthritic joints, but its direct effects are not known. Here, we investigated MCT-evoked acute inflammatory and nociceptive mechanisms with behavioural, in vivo imaging and immunological techniques.

Material and subjects

Neurogenic inflammation involving capsaicin-sensitive afferents, transient receptor potential vanilloid 1 receptor (TRPV1), substance P (SP), neurokinin A (NKA) and their NK1 tachykinin receptor were studied using gene-deleted mice compared to C57Bl/6 wildtypes (n = 5–8/group).

Treatment

MCT was administered intraarticularly or topically (20 μl, 12 μg/ml). Capsaicin-sensitive afferents were defunctionalized with the TRPV1 agonist resiniferatoxin (RTX; 30–70–100 μg/kg s.c. pretreatment).

Methods

Knee diameter was measured with a caliper, synovial perfusion with laser Doppler imaging, mechanonociception with aesthesiometry and weight distribution with incapacitance tester over 6 h. Cytokines and neuropeptides were determined with immunoassays.

Results

MCT induced synovial vasodilatation, oedema, impaired weight distribution and mechanical hyperalgesia, but cytokine or neuropeptide levels were not altered at the 6-h timepoint. Hyperaemia was reduced in RTX-treated and TRPV1-deleted animals, and oedema was absent in NK1-deficient mice. Hyperalgesia was decreased in SP/NKA- and NK1-deficient mice, weight bearing impairment in RTX-pretreated, TRPV1- and NK1-deficient animals.

Conclusions

MCT evokes synovial hyperaemia, oedema, hyperalgesia and spontaneous pain. Capsaicin-sensitive afferents and TRPV1 receptors are essential for vasodilatation, while tachykinins mediate oedema and pain.

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Abbreviations

CGRP:

Calcitonin gene-related peptide

IL-1β:

Interleukin-1β

MCT:

Mast cell tryptase

NK1:

Tachykinin NK1 receptor

NKA:

Neurokinin A

PAR2:

Protease-activated receptor 2

TRPV1:

Transient receptor potential vanilloid 1

RTX:

Resiniferatoxin

SP:

Substance P

Tac1:

Preprotachykinin 1 gene

Tacr1:

Tachykinin NK1 receptor encoding gene

TNFα:

Tumour necrosis factor α

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Acknowledgments

This work was supported by KTIA_NAP_13-2014-0022 (MTA-PTE NAP B Pain Research Group, identification number: 888819, Zs. Helyes) and OTKA NN-114458 (E. Pintér). The present scientific contribution is dedicated to the 650th anniversary of the foundation of the University of Pécs, Hungary. The authors are grateful to Teréz Bagoly for the CGRP and SP measurements.

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Authors and Affiliations

  1. Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti u. 12, Pecs, 7624, Hungary

    Éva Borbély, Katalin Sándor, Adrienn Markovics, Ágnes Kemény, Erika Pintér, János Szolcsányi & Zsuzsanna Helyes

  2. János Szentágothai Research Centre, Molecular Pharmacology Research Group, Centre for Neuroscience, University of Pécs, Pecs, Hungary

    Éva Borbély, Adrienn Markovics, Ágnes Kemény, Erika Pintér, János Szolcsányi & Zsuzsanna Helyes

  3. MTA-PTE NAP B Chronic Pain Research Group, Pecs, Hungary

    Zsuzsanna Helyes

  4. School of Biomedical Sciences, Liverpool University, Liverpool, UK

    John P. Quinn

  5. Department of Pharmacology, Dalhousie University, Halifax, NS, Canada

    Jason J. McDougall

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  1. Éva Borbély
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Borbély, É., Sándor, K., Markovics, A. et al. Role of capsaicin-sensitive nerves and tachykinins in mast cell tryptase-induced inflammation of murine knees. Inflamm. Res. 65, 725–736 (2016). https://doi.org/10.1007/s00011-016-0954-x

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