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. 2017 Aug 17;12(8):e0183322.
doi: 10.1371/journal.pone.0183322. eCollection 2017.

Short Report: TRPV1-polymorphism 1911 A>G alters capsaicin-induced sensory changes in healthy subjects

Julia Forstenpointner  1 , Matti Förster  1   2 , Denisa May  3 , Friederike Hofschulte  1 , Ingolf Cascorbi  3 , Gunnar Wasner  1   4 , Janne Gierthmühlen  1 , Ralf Baron  1
Affiliations

Short Report: TRPV1-polymorphism 1911 A>G alters capsaicin-induced sensory changes in healthy subjects

Julia Forstenpointner et al. PLoS One. .

Abstract

Background: C-fibers express transient receptor potential (TRP) channels. These high-voltage gated channels function as integrators of different physical stresses (e.g. heat, protons, ATP). Additionally channel activation can be induced by capsaicin. Topically applied, capsaicin elicits burning pain, heat and mechanical hyperalgesia and serves as a human surrogate model for pain. It was suggested that the TRPV1-variant rs8065080 (1911A>G) plays a pivotal role in patients with neuropathic pain syndromes. We investigated the effect of this TRPV1-SNP on thermal sensitivity and superficial skin perfusion in 25 healthy subjects.

Methods and findings: Nine subjects being homozygous TRPV1 wild type (AA), 8 heterozygous (AG) and 8 homozygous variant (GG) carriers were selected out of a pool of genotyped healthy individuals. Under physiological conditions (no capsaicin application), there was no statistical significant difference in thermal thresholds or skin perfusion between carriers of different TRPV1 1199A>G genotypes. However, intra-individual calculations (Δ% pre vs. post capsaicin) revealed (1) less warm-detection in AA/AG (-82.1%) compared to GG (-13.1%) and (2) a gain of heat pain sensitivity in AA/AG (+22.2%) compared to GG carriers (+15.6%) after adjustment for perfusion measurements ((1)p = 0.009, (2)p = 0.021).

Conclusion: Presence of homozygous variant TRPV1 genotype (GG) demonstrated less capsaicin-induced warm hypoesthesia in warm-detection and less capsaicin-induced heat pain sensitivity suggesting an altered channel function. This demonstrates not only the functional influence of TRPV1 rs8065080 polymorphism itself; it further more underpins the relevance of genotyping-based approaches in both patients and surrogate models of neuropathic pain in healthy volunteers.

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Conflict of interest statement

Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests. MF and DM do not declare competing interests. JF receives research support from Grünenthal as well as speaker fees and/or travel support from Grünenthal, Sanofi Genzyme and Bayer. FH is a member of the IMI "Europain" consortium. She has received research support, consulting, or speaking fees from Grünenthal and Pfizer. IC has been a consultant to Astellas, Medac and Zogenix. GW received speaking fees from Astellas, Grünenthal, Pfizer and Mundipharma. RB has received grants / research support from Pfizer, Genzyme GmbH, Grünenthal GmbH, Mundipharma. He is a member of the EU Project No 633491: DOLORisk. A member of the IMI „Europain" collaboration (grant agreement 115007) and industry members of this are: Astra Zeneca, Pfizer, Esteve, UCB-Pharma, Sanofi Aventis, Grünenthal GmbH, Eli Lilly and Boehringer Ingelheim Pharma GmbH&Co.KG. German Federal Ministry of Education and Research (BMBF): Member of the ERA-NET NEURON / IM-PAIN Project (01EW1503). German Research Network on Neuropathic Pain (01EM0903), NoPain system biology (0316177C). German Research Foundation (DFG). He has received speaking fees from Pfizer, Genzyme GmbH, Grünenthal GmbH, Mundipharma, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai Co.Ltd., Lilly GmbH, Boehringer Ingelheim Pharma GmbH&Co.KG, Astellas, Desitin, Teva Pharma, Bayer-Schering, MSD GmbH, Seqirus. He has been a consultant for Pfizer, Genzyme GmbH, Grünenthal GmbH, Mundipharma, Allergan, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai Co.Ltd., Lilly GmbH, Boehringer Ingelheim Pharma GmbH&Co.KG, Astellas, Novartis, Bristol-Myers- Squibb, Biogenidec, AstraZeneca, Merck, Abbvie, Daiichi Sankyo, Glenmark Pharmaceuticals, Seqirus, Teva Pharma, Genentech, Galapagos NV and Kyowa Kirin GmbH. JG has received speaker fees and travel support from Pfizer, Grünenthal, Sanofi Pasteur MSD GmbH, TAD Pharma and consultancy fees from Glenmark. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Laser Doppler measurement.
a) Sample image of Laser Doppler measurement setup. Regions of interest (ROI) were created around the capsaicin patch stimulation area for further calculations. The intensity image depicts the color-coded perfusion magnitude. b) Area of elevated skin perfusion (flare) was measured in mm2. There was no significant difference between the genotypes, however a trend towards smaller flare areas in 1911 GG carriers can be observed. c-d) Perfusion changes during capsaicin application were measured via Laser Doppler flowmetry. There was no significant difference between the genotypes, but a trend towards a decreased perfusion gain in 1911 GG carriers.
Fig 2
Fig 2. Thermal quantitative sensory testing of TRPV1 variants.
Comparison of intra-individual data (Δ%change prior vs. after capsaicin) of homozygous G (1911GG) against homozygous and heterozygous A carriers (1911AA+1911AG) reveals lower changes (1) towards loss of warm detection in GG (13.1%) compared to AA/AG (82.1%) and (2) towards gain of heat pain sensitivity in GG (15.6%) compared to AA/AG (22.2%) ((1) p = 0.009; (2) p = 0.021). Note: Data are displayed as means (±SEM) for all analyzed patients. P<0.05 considered significance. ((1)Mann-Whitney U test, (2)ANCOVA). *p<0.05; **p<0.01.
See this image and copyright information in PMC

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