2. Academic Validation
  3. Inhibition of TRPM8 by the urinary tract analgesic drug phenazopyridine

Inhibition of TRPM8 by the urinary tract analgesic drug phenazopyridine

  • Eur J Pharmacol. 2023 Mar 5:942:175512. doi: 10.1016/j.ejphar.2023.175512.
Noémie Luyts 1,  Jan Daniluk 2,  Ana Cristina Nogueira Freitas 3,  Bahar Bazeli 4,  Annelies Janssens 5,  Marie Mulier 6,  Wouter Everaerts 7,  Thomas Voets 8
Affiliations

Affiliations

  • 1 Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium. Electronic address: [email protected].
  • 2 Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium. Electronic address: [email protected].
  • 3 Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium. Electronic address: [email protected].
  • 4 Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium. Electronic address: [email protected].
  • 5 Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium. Electronic address: [email protected].
  • 6 Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium. Electronic address: [email protected].
  • 7 Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium; Department of Urology, University Hospitals Leuven, Leuven, Belgium. Electronic address: [email protected].
  • 8 Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium. Electronic address: [email protected].
PMID: 36657655 DOI: 10.1016/j.ejphar.2023.175512
Abstract

Background: and purpose: Phenazopyridine (PAP) is an over-the-counter drug widely used to provide symptomatic relief of bladder pain in conditions such as cystitis or bladder pain syndrome (BPS). Whereas the analgesic effect of PAP has been attributed to a local effect on the mucosa of the lower urinary tract (LUT), the molecular targets of PAP remain unknown. We investigated the effect of PAP on pain-related Transient Receptor Potential (TRP) channels expressed in sensory neurons that innervate the bladder wall.

Experimental approach: The effects of PAP on the relevant TRP channels (TRPV1, TRPA1, TRPM8, TRPM3) expressed in HEK293 or CHO cells was investigated using Fura-2-based calcium measurements and whole-cell patch-clamp recordings. Activity of PAP on TRPM8 was further analysed using Fura-2-based calcium imaging on sensory neurons isolated from lumbosacral dorsal root ganglia (DRG) of mice.

Key results: PAP rapidly and reversibly inhibits responses of TRPM8 expressed in HEK293 cells to cold and menthol, with IC50 values between 2 and 10 μM. It acts by shifting the voltage dependence of channel activation towards positive potentials, opposite to the effect of menthol. PAP also inhibits TRPM8-mediated, menthol-evoked calcium responses in lumbosacral DRG neurons. At a concentration of 10 μM, PAP did not significantly affect TRPA1, TRPV1, or TRPM3.

Conclusion and implications: PAP inhibits TRPM8 in a concentration range consistent with PAP levels in the urine of treated patients. Since TRPM8 is expressed in bladder afferent neurons and upregulated in patients with painful bladder disorders, TRPM8 inhibition may underlie the analgesic activity of PAP.

Keywords

Analgesia; Molecular target; Phenazopyridine; TRPM8; Urinary tract.

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