Inhibition of TRPM8 by the urinary tract analgesic drug phenazopyridine.
Animals
Cricetinae
Humans
Mice
Calcium
/ metabolism
Cricetulus
Fura-2
/ pharmacology
Ganglia, Spinal
/ metabolism
HEK293 Cells
Menthol
/ pharmacology
Pain
Phenazopyridine
/ pharmacology
Sensory Receptor Cells
/ metabolism
Transient Receptor Potential Channels
TRPA1 Cation Channel
TRPM Cation Channels
Urinary Bladder
/ metabolism
Analgesia
Molecular target
Phenazopyridine
TRPM8
Urinary tract
Journal
European journal of pharmacology
ISSN: 1879-0712
Titre abrégé: Eur J Pharmacol
Pays: Netherlands
ID NLM: 1254354
Informations de publication
Date de publication:
05 Mar 2023
05 Mar 2023
Historique:
received:
05
10
2022
revised:
11
01
2023
accepted:
13
01
2023
pubmed:
20
1
2023
medline:
14
2
2023
entrez:
19
1
2023
Statut:
ppublish
Résumé
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. 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. PAP rapidly and reversibly inhibits responses of TRPM8 expressed in HEK293 cells to cold and menthol, with IC 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.
Sections du résumé
BACKGROUND
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
METHODS
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
RESULTS
PAP rapidly and reversibly inhibits responses of TRPM8 expressed in HEK293 cells to cold and menthol, with IC
CONCLUSION AND IMPLICATIONS
CONCLUSIONS
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.
Identifiants
pubmed: 36657655
pii: S0014-2999(23)00023-7
doi: 10.1016/j.ejphar.2023.175512
pii:
doi:
Substances chimiques
Calcium
SY7Q814VUP
Fura-2
TSN3DL106G
Menthol
1490-04-6
Phenazopyridine
K2J09EMJ52
Transient Receptor Potential Channels
0
TRPA1 Cation Channel
0
TRPM Cation Channels
0
TRPM3 protein, mouse
0
TRPM8 channel-associated factor 1 protein, human
0
TRPM8 protein, human
0
TRPM8 protein, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
175512Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.