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Molecular Neurobiology

, Volume 56, Issue 1, pp 444–453 | Cite as

TRPV4-Mediated Anti-nociceptive Effect of Suberanilohydroxamic Acid on Mechanical Pain

  • Geunyeol Choi
  • Tae-Jin Yang
  • Sungjae Yoo
  • Seung-In Choi
  • Ji Yeon Lim
  • Pyung Sun Cho
  • Sun Wook HwangEmail author
Article

Abstract

Biological effects of suberanilohydroxamic acid (SAHA) have mainly been observed in the context of tumor suppression via epigenetic mechanisms, but other potential outcomes from its use have also been proposed in different fields such as pain modulation. Here, we tried to understand whether SAHA modulates specific pain modalities by a non-epigenetic unknown mechanism. From 24 h Complete Freund’s Adjuvant (CFA)-inflamed hind paws of mice, mechanical and thermal inflammatory pain indices were collected with or without immediate intraplantar injection of SAHA. To examine the action of SAHA on sensory receptor-specific pain, transient receptor potential (TRP) ion channel-mediated pain indices were collected in the same manner of intraplantar treatment. Activities of primarily cultured sensory neurons and heterologous cells transfected with TRP channels were monitored to determine the molecular mechanism underlying the pain-modulating effect of SAHA. As a result, immediate and localized pretreatment with SAHA, avoiding an epigenetic intervention, acutely attenuated mechanical inflammatory pain and receptor-specific pain evoked by injection of a TRP channel agonist in animal models. We show that a component of the mechanisms involves TRPV4 inhibition based on in vitro intracellular Ca2+ imaging and electrophysiological assessments with heterologous expression systems and cultured sensory neurons. Taken together, the present study provides evidence of a novel off-target action and its mechanism of SAHA in its modality-specific anti-nociceptive effect and suggests the utility of this compound for pharmacological modulation of pain.

Keywords

SAHA Pain TRPV4 Non-epigenetic mechanism 

Notes

Acknowledgements

This work was supported by grants from the National Research Foundation of Korea (2017R1A2B2001817 and 2017M3C7A1025600) and Korea Health technology R&D Project of Ministry of Health & Welfare (HI15C2099).

Author Contributions

GC and TJY carried out the experiments and analyzed the data. TJY and GC wrote the preliminary draft. SY, SIC, JYL, and PSC assisted the experiments and contributed to the result interpretations. SWH supervised the studies and wrote the manuscript. All authors read and approved the final manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_1093_MOESM1_ESM.pdf (60 kb)
Supplementary Figure 1 Effects of SAHA pretreatment on TRPV1-mediated acute behavioral nociception in PGE2-primed animals. (A) Summary of the time course of licking/flicking behaviors in mice treated with capsaicin (100 μM in 10 μl). The behavioral responses occurred immediately after hind paw intraplantar injection of capaicin (n = 5, gray circle). When the hind paws were primed with 100 ng PGE2 30 min before injection of capsaicin, the mice also began to show licking/flicking behaviors in response to injection of capsaicin (n = 5, black circle). The data from the mice treated with SAHA (100 μM in 10 μl) 1 min prior to the capsaicin administration were shown with filled squares (n = 5). (B) Summary histograms of the accumulated time engaged in the nociceptive behaviors in (A). (PDF 60 kb)
12035_2018_1093_MOESM2_ESM.pdf (63 kb)
Supplementary Figure 2 SAHA reverses lowered mechanical thresholds but not heat thresholds in 4αPDD-primed animals. (A) Summary of changes in the mechanical thresholds from von-Frey tests with SAHA pretreatment. The von-Frey threshold was decreased 1 h after 4αPDD injection (n = 5) to 64% compared to the control threshold (n = 5). When treated with SAHA (100 μM) 1 min before threshold observation, the threshold decreases were reversed (85% compared to the control threshold, n = 5). (B) Summary of the changes in the hind paw withdrawal thresholds from Randall-Selitto tests with SAHA treatment. The Randall-Selitto threshold was decreased 1 h after 4αPDD injection (n = 5) to 47% (control, n = 5). When treated with SAHA (100 μM) 1 min before latency observation, the latency decreases were reversed (69% compared to the control threshold, n = 5). (C) Summary of the changes in paw withdrawal latencies from Hargreaves tests by SAHA pretreatment. The Hargreaves latency was decreased 1 h after 4αPDD injection (n = 5) to 26% (control, n = 5). No significant change in the latency was observed upon intraplantar SAHA treatment (100 μM, n = 5). (PDF 62 kb)
12035_2018_1093_MOESM3_ESM.pdf (67 kb)
Supplementary Figure 3 4αPDD does not alter intracellular Ca2+ levels in non-transfected HEK293T cells. (A) Representative time-lapse images showing Fura-2 fluorescence indicating intracellular Ca2+ levels normalized to the initial values. (B) Summary histograms of the averaged peak Ca2+ level from experiments including (A). Experiments are triplicated (n = 98). (PDF 67 kb)
12035_2018_1093_MOESM4_ESM.pdf (58 kb)
Supplementary Figure 4 Size analysis on the soma diameters of neurons that responded to GSK1019790 in fig. 5B and D. (A) Number of neurons that responded to GSK1019790 in fig. 5B and D are counted according to the soma diameters. Open bars represent the collection of SAHA-insensitive neurons and filled bars represent the collection of SAHA-sensitive neurons. (B) Summary histograms of the averaged diameters from of SAHA-insensitive (n = 32, open bar) and SAHA-sensitive neurons (n = 40, closed bar). (PDF 58 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biomedical SciencesKorea University College of MedicineSeoulSouth Korea
  2. 2.Department of PhysiologyKorea University College of MedicineSeoulSouth Korea

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