Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2020 Jul;161(7):1532-1541.
doi: 10.1097/j.pain.0000000000001848.

TRPV1 antagonist BCTC inhibits pH 6.0-induced pain in human skin

Stefan Heber  1 , Cosmin I Ciotu  1 , Gabriel Hartner  1 , Markus Gold-Binder  1 , Nino Ninidze  2 , Andreas Gleiss  3 , Hans-Georg Kress  2 , Michael J M Fischer  1
Affiliations
Randomized Controlled Trial

TRPV1 antagonist BCTC inhibits pH 6.0-induced pain in human skin

Stefan Heber et al. Pain. 2020 Jul.

Abstract

Tissue acidosis due to ischemia occurs under several pathological conditions and is believed to contribute to pain in these circumstances. TRPV1, TRPA1, and ASICs are known to be sensitive to acidic pH. Addressing their possible role in acidosis perception, the respective antagonists BCTC, A-967079, and amiloride were injected in the volar forearm skin of 32 healthy volunteers. To investigate possible redundancies between channels, a full-factorial study design was used. Injections were performed in a prerandomized, double-blind, and balanced design. Each injection included a three-step pH protocol from pH 7.0 over pH 6.5 to pH 6.0 with a step duration of 90 seconds. Pain was reported by volunteers on a numerical scale every 10 seconds during injections. Confirming the primary hypothesis, the combination of all 3 antagonists reduced acid-induced pain at pH 6.0. Because of the full-factorial design, it could be concluded that BCTC alone, but not A-967079 or amiloride, or any combination thereof, was responsible for the observed effects, suggesting TRPV1 as primary sensor for pH 6.0-induced pain. Surprisingly, A-967079 even enhanced pain induced by pH 6.0. In cultured mouse dorsal root ganglion neurons, TPRV1 dependence of pH 6-induced calcium responses could be confirmed. Responses of hTRPV1 to acidic stimulation showed a maximum around pH6, providing an explanation for the pH-dependent inhibition by BCTC. A-967079 sensitizes pH responses is a TRPA1-responsive dorsal root ganglion neuron population, and a direct effect of A-967079 on hTRPA1 and hTRPV1 was excluded. In conclusion, inhibiting TRPV1-mediated acidosis-induced pain could be a symptomatic and potentially also a disease-modifying approach.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Andersson DA, Gentry C, Alenmyr L, Killander D, Lewis SE, Andersson A, Bucher B, Galzi JL, Sterner O, Bevan S, Hogestatt ED, Zygmunt PM. TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Delta(9)-tetrahydrocannabiorcol. Nat Commun 2011;2:551.
    1. Aneiros E, Cao L, Papakosta M, Stevens EB, Phillips S, Grimm C. The biophysical and molecular basis of TRPV1 proton gating. EMBO J 2011;30:994–1002.
    1. Auer J, Reeh PW, Fischer MJ. Acid-induced CGRP release from the stomach does not depend on TRPV1 or ASIC3. Neurogastroenterol Motil 2010;22:680–7.
    1. Bretag AH. Synthetic interstitial fluid for isolated mammalian tissue. Life Sci 1969;8:319–29.
    1. de la Roche J, Eberhardt MJ, Klinger AB, Stanslowsky N, Wegner F, Koppert W, Reeh PW, Lampert A, Fischer MJ, Leffler A. The molecular basis for species-specific activation of human TRPA1 protein by protons involves poorly conserved residues within transmembrane domains 5 and 6. J Biol Chem 2013;288:20280–92.

Publication types

LinkOut - more resources