Ectopic endometriosis in the pelvic cavity evokes bladder hypersensitivity via transient receptor potential ankyrin 1 hyperexpression in rats

Introduction and hypothesis In women with chronic pelvic pain (CPP), interstitial cystitis/bladder pain syndrome (IC/BPS) and endometriosis frequently coexist. The mechanism of these diseases coexisting is explained by cross-sensitization between endometriosis and IC/BPS. The overlapped symptoms may be related to cross-sensitization with transient receptor potential vanilloid 1 (TRPV1) and/or transient receptor potential ankyrin 1 (TRPA1) hyperexpression. This study was aimed at exploring whether bladder hypersensitivity is evoked in the surgically induced ectopic endometriosis rat and whether TRPV1 and/or TRPA1 play a vital role.

A total of 63 Sprague–Dawley female rats were divided into two groups, 39 for physiological examination and 24 for molecular analysis. Surgical induction of ectopic endometriosis (ENDO, n=27), surgical sham treatment (n=18), and treatment for endometriosis by GnRH analog (ENDO-G) (n=18) were performed. Bladder function was investigated by cystometry (for TRPV1 in the sham [n=6] and ENDO [n=9] groups and for TRPA1 in the sham [n=6], ENDO [n=9], and ENDO+G [n=9] groups), and TRPV1 and TRPA1 mRNA expressions were measured using real-time qPCR in the bladder and dorsal root ganglia (DRGs).

On cystometry, the relative intercontraction interval (ICI) after/before resiniferatoxin (RTx; TRPV1 activator) infusion to the bladder showed no significant difference between the two groups, whereas relative ICI after/before allyl isothiocyanate (AITC; TRPA1 activator) infusion was significantly lower in the ENDO group than in the sham group. TRPA1 mRNA expression in the bladder and L5 DRG was considerably higher in the ENDO group than in the sham group on real-time qPCR. TRPA1 mRNA hyperexpression and bladder hypersensitivity after AITC infusion were reduced in the ENDO-G group.

Bladder cross-sensitization in ENDO rats occurs in association with hyperexpression of TRPA1 at both the DRG and the bladder mucosa. This can be understood by the “cross-sensitization of endometriosis to bladder” theory explaining overlapping symptoms among BPS/IC and ectopic endometriosis. Similar content being viewed by others Abbreviations - AITC: - Allyl isothiocyanate - CPP: - Chronic pelvic pain - DMSO: - Dimethyl sulfoxide - DRG: - Dorsal root ganglion - ENDO: - Endometriosis - IBS: - Irritable bowel syndrome - IC/BPS: - Interstitial cystitis/bladder pain syndrome - ICI: - Intercontraction interval - qPCR: - Quantitative polymerase chain reaction - RTx: - Resiniferatoxin - TRPA1: - Transient receptor potential ankyrin 1 - TRPV1: - Transient receptor potential vanilloid 1

Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Neurourol Urodyn. 2002;21(2):178. Paulson JD, Delgado M. Chronic pelvic pain: The occurrence of interstitial cystitis in a gynecological population. JSLS. 2005;9(4):426–30. Wu C. Endometriosis increased the risk of bladder pain syndrome/interstitial cystitis: a population-based study. Neurourol Urodyn. 2017;37(4):1–6. Chung MK, Chung RP, Gordon D. Interstitial cystitis and endometriosis in patients with chronic pelvic pain: the “Evil Twins” syndrome. JSLS. 2005;9(1):25–9. Malykhina AP. Neural mechanisms of pelvic organ cross-sensitization. Neuroscience. 2007;149(3):660–72. Yoshikawa S, Kawamorita N, Oguchi T, et al. Pelvic organ cross-sensitization to enhance bladder and urethral pain behaviors in rats with experimental colitis. Neuroscience. 2015;284:422–9. Saitoh C, Chancellor MB, de Groat WC, Yoshimura N. Effects of intravesical instillation of resiniferatoxin on bladder function and nociceptive behavior in freely moving, conscious rats. J Urol. 2008;179(1):359–64. Furuta A, Suzuki Y, Naruoka T, et al. Cross-sensitization mechanisms between colon and bladder via transient receptor potential A1 stimulation in rats. Int Urogynecol J. 2014;25(11):1575–81. Kawamorita N, Yoshikawa S, Kashyap M, et al. Liposome based intravesical therapy targeting nerve growth factor ameliorates bladder hypersensitivity in rats with experimental colitis. J Urol. 2016;195(6):1920–6. Wyndaele M, De Wachter S, De Man J, et al. Mechanisms of pelvic organ crosstalk: 1. Peripheral modulation of bladder inhibition by colorectal distention in rats. J Urol. 2013;190(2):765–71. Morrison TC, Dmitrieva N, Winnard KP, Berkley KJ. Opposing viscerovisceral effects of surgically induced endometriosis and a control abdominal surgery on the rat bladder. Fertil Steril. 2006;86(4 Suppl):1067–73. Streng T, Hedlund P, Talo A, et al. Phasic non-micturition contractions in the bladder of the anesthetized and awake rat. BJU Int. 2006;97(5):1094–101. Triolo O, Laganà AS, Sturlese E. Chronic pelvic pain in endometriosis: an overview. J Clin Med Res. 2013;5(3):153–63. Bohonyi N, Pohóczky K, Szalontai B, et al. Local upregulation of transient receptor potential ankyrin I and transient receptor potential vanilloid I ion channels in rectosigmoid deep infiltrating endometriosis. Mol Pain. 2017;13:1–13. Altintas D, Kokcu A, Tosun M, et al. Comparison of the effects of cetrorelix, a GnRH antagonist, and leuprolide, a GnRH agonist, on experimental endometriosis. J Obstet Gynaecol Res 2008;34(6):1014–19 Streng T, Axelsson HE, Hedlund P, et al. Distribution and function of the hydrogen sulfide-sensitive TRPA1 ion channel in rat urinary bladder. Eur Urol. 2008;53(2):391–400. Lian YL, Cheng MJ, Zhang XX, Wang L. Elevated expression of transient receptor potential vanilloid type 1 in dorsal root ganglia of rats with endometriosis. Mol Med Rep. 2017;16(2):1920–6. Gouin O, Lebonvallet N, Le Gall-Ianotto C, et al. TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization. Protein Cell. 2017;8(9):644–61. Trevisani M, Siemens J, Materazzi S, et al. 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A. 2007;104(33):13519–24. Pozsgai G, Hajna Z, Bagoly T, et al. The role of transient receptor potential ankyrin 1 (TRPA1) receptor activation in hydrogen-sulphide-induced CGRP-release and vasodilation. Eur J Pharmacol. 2012;689(1–3):56–64.

The authors are very grateful to Ms. Natsue Abe and Ms. Azusa Sasaki for technical assistance. Author information Authors and Affiliations Contributions Natsuho Hayashi: data collection/analysis, manuscript writing; Naoki Kawamorita: protocol development, data analysis, manuscript writing/editing; Yuichi Ishizuka: data collection/analysis; Shingo Kimura: data collection/analysis; Yohei Satake: protocol development, data collection/analysis; Akihiro Ito: protocol development, manuscript editing. Corresponding author Ethics declarations Conflicts of interest None. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Hayashi, N., Kawamorita, N., Ishizuka, Y. et al. Ectopic endometriosis in the pelvic cavity evokes bladder hypersensitivity via transient receptor potential ankyrin 1 hyperexpression in rats. Int Urogynecol J 34, 1211–1218 (2023). https://doi.org/10.1007/s00192-022-05335-x Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s00192-022-05335-x