The Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) are non-selective cation channels predominantly localized on capsaicin-sensitive sensory neurons; however both receptors have been described in non-neuronal tissues. It has been published that both receptors upregulated in peritoneal endometriosis in humans. Our research group demonstrated that TRPA1 and TRPV1 expression is elevated in human deep infiltrating endometriosis (DIE) lesions and the receptors have an estrogen-dependent expression pattern in rat endometrium. Here, we investigated the expression changes of TRPA1/V1 and the role of the capsaicin-sensitive sensory-nerve endings in a rat model of peritoneal endometriosis. Peritoneal endometriosis was surgically induced in 8-week-old female rats (n=7-7) for 2-weeks (acute condition) and 8-weeks (chronic condition). TRPA1/V1 mRNAs were quantified with quantitative polymerase chain reaction (qPCR). The expression levels were compared with the results obtained earlier from human DIE samples. The blockade of the TRPA1/V1 expressing capsaicin-sensitive nerve endings was induced with resiniferatoxin (RTX), followed by the measurement of the weight and size of the endometriosis lesions. We detected TRPV1 and TRPA1 mRNA in normal rat endometrium, their expression was not altered in sham-operated animals. In chronic, but not in acute endometriosis the expression was significantly elevated in the lesions, which results are consistent with our previous findings in human DIE. The elimination of capsaicin-sensitive nerve endings decreased the weight of the endometriosis lesions while the size of the ectopic tissue was not altered. Taken together, our results obtained from the rat endometriosis model are consistent with the previous human results, therefore this model is considered to have translational significance and it is suitable for functional analysis of the ion channels. The local, non-neuronal TRPA1 and TRPV1 might play a role in inflammation and sensory neuronal activation in endometriosis related pain, which is mediated by a broad range of pro-inflammatory molecules.
4. Jenkins TR, Liu CY, White J. Does Response to Hormonal Therapy Predict Presence or Absence of Endometriosis ? J Minim Invasive Gynecol. 2018;5(1):82–6.
5. Jones KD, Haines P, Sutton CJ. Long-term follow-up of a controlled trial of laser laparoscopy for pelvic pain. JSLS J Soc Laparoendosc Surg [Internet]. 2001;5(2):111–5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11394422
7. Baraldi P. G., Preti D., Materazzi S., Geppetti P. Transient Receptor Potential Ankyrin 1 (TRPA1) Channel as Emerging Target for Novel Analgesics and Anti-Inflammatory Agents. J Med Chem [Internet]. 2010;53(14):5085–107. Available from: http://dx.doi.org/10.1021/jm100062h
8. Fernandes E. S., Fernandes M. A., Keeble J. E. The functions of TRPA1 and TRPV1: Moving away from sensory nerves. Br J Pharmacol. 2012;166(2):510–21.
9. Caterina M. J., Schumacher M. A., Tominaga M., Rosen T. A., D. LJ, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389(6653):816–24.
10. Rocha MG, Silva JCR e, Ribeiro da Silva A, Candido Dos Reis FJ, Nogueira AA, Poli-Neto OB. TRPV1 Expression on Peritoneal Endometriosis Foci is Associated With Chronic Pelvic Pain. Reprod Sci [Internet]. 2011 Jun 1;18(6):511–5. Available from: http://rsx.sagepub.com/content/18/6/511.abstract
11. Liu J, Liu X, Duan K, Zhang Y, Guo S-W. The Expression and Functionality of Transient Receptor Potential Vanilloid 1 in Ovarian Endometriomas. Reprod Sci [Internet]. 2012 Oct 1;19(10):1110–24. Available from: http://rsx.sagepub.com/content/19/10/1110.abstract
12. Kark T., Bagi Zs., Lizanecz E., Pásztor E. T., Erdei N., Czikora Á., et al. Tissue-specific regulation of microvascular diameter: opposite functional roles of neuronal and smooth muscle located vanilloid receptor-1. Mol Pharmacol. 2008;73(5):1405–12.
13. Greaves E., Grieve K., Horne A. W., Saunders P. T. Elevated peritoneal expression and estrogen regulation of nociceptive ion channels in endometriosis. J Clin Endocrinol Metab. 2014;99(July):jc20142282. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25029427
15. Telfer J. F., Irvine G. A., Kohnen G., Campbell S., Cameron I. T. Expression of endothelial and inducible nitric oxide synthase in non-pregnant and decidualized human endometrium. Mol Hum Reprod. 1997;3(1):69–75. Available from: http://molehr.oxfordjournals.org/content/3/1/69.abstract
16. Mizuno K., Tanaka T., Umesaki N., Ogita S. Inhibition of cAMP-mediated decidualization in human endometrial stromal cells by IL-1beta and laminin. Horm Metab Res = Horm und Stoffwechselforsch = Horm métabolisme. 1999;31(5):307–10.
17. Wira C. R., Fahey J. V., Ghosh M., Patel M. V., Hickey D. K., Ochiel D. O. Sex Hormone Regulation of Innate Immunity in the Female Reproductive Tract: The Role of Epithelial Cells in Balancing Reproductive Potential with Protection against Sexually Transmitted Pathogens. Am J Reprod Immunol. 2010;63(6):10.1111/j.1600-0897.2010.00842.x. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837356/
18. Szállási A., Szolcsányi J., Szállási Z., Blumberg PM: Inhibition of [ 3H ] resiniferatoxin binding to rat dorsal root ganglion m ... compounds with capsaicin-like activity . Naunyn Schmiedebergs Arch Pharmacol. 1991;344(5):172–81.
19. Pelch KE, Sharpe-Timms KL, Nagel SC. Mouse model of surgically-induced endometriosis by auto-transplantation of uterine tissue. J Vis Exp [Internet]. 2012 Jan 6;(59):e3396–e3396. Available from: https://www.ncbi.nlm.nih.gov/pubmed/22257948
20. Ohtori S, Chiba T, Takahashi K, Ino H, Yamagata M, Sameda H, et al. Neonatal capsaicin treatment decreased substance P receptor immunoreactivity in lamina III neurons of the dorsal horn. Neurosci Res. 2000;38(2):147–54.
21. Vyklický L, Benedikt J, Samad A, Touška F, Vlachová V. Calcium-Dependent Desensitization of Vanilloid Receptor TRPV1 : A Mechanism Possibly Involved in Analgesia Induced by Topical Application of Capsaicin. 2008;57.
22. Borbely E, Botz B, Bolcskei K, Kenyer T, Kereskai L, Kiss T, et al. Capsaicin-sensitive sensory nerves exert complex regulatory functions in the serum-transfer mouse model of autoimmune arthritis. Brain Behav Immun. 2015 Mar;45:50–9.
24. Hornstein MD, Gleason RE, Orav J, Haas ST, Friedman AJ, Rein MS, et al. The reproducibility of the revised American Fertility Society classification of endometriosis *. Fertil Steril. 2016 Jul 5;59(5):1015–21. Available from: http://dx.doi.org/10.1016/S0015-0282(16)55921-4
25. Bohonyi N, Pohóczky K, Szalontai B, Perkecz A, Kovács K, Kajtár B, et al. Local upregulation of transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1 ion channels in rectosigmoid deep infiltrating endometriosis. Mol Pain. 2017 May 7;13:1744806917705564–1744806917705564. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28478727
26. Szolcsányi J., Pintér E., Helyes Zs., Oroszi G., Németh J. Systemic anti-inflammatory effect induced by counter-irritation through a local release of somatostatin from nociceptors. Br J Pharmacol. 1998;125(4):916–22.
27. Liu J., Liu X., Duan K., Zhang Y., Guo S.-W. The Expression and Functionality of Transient Receptor Potential Vanilloid 1 in Ovarian Endometriomas. Reprod Sci. 2012;19(10):1110–24.
28. Rocha MG, Gomes VA, Tanus-Santos JE, Rosa-e-Silva JC, Candido-dos-Reis FJ, Nogueira AA, et al. Reduction of blood nitric oxide levels is associated with clinical improvement of the chronic pelvic pain related to endometriosis. Vol. 48, Brazilian Journal of Medical and Biological Research. scielo; 2015. p. 363–9.
29. Suzuki M., Sugimoto H., Nakagawa A., Tanaka I., Nishihira J., Sakai M. Crystal structure of the macrophage migration inhibitory factor from rat liver. Nat Struct Mol Biol. 1996;3(3):259–66.
30. Akoum A., Metz C. N., Al-Akoum M., Kats R. Macrophage migration inhibitory factor expression in the intrauterine endometrium of women with endometriosis varies with disease stage, infertility status, and pelvic pain. Fertil Steril. 2006;85(5):1379–85. Available from: http://www.sciencedirect.com/science/article/pii/S0015028206002263
31. Greaves E, Temp J, Esnal-Zufiurre A, Mechsner S, Horne AW, Saunders PTK. Estradiol Is a Critical Mediator of Macrophage-Nerve Cross Talk in Peritoneal Endometriosis. Am J Pathol. 2015 Aug 16;185(8):2286–97. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530129/
33. Poli-Neto O. B., Adnor Filho A., e Silva J. C. R., de Freitas Barbosa H., Dos Reis F. J. C., Nogueira A. A. Increased capsaicin receptor TRPV1 in the peritoneum of women with chronic pelvic pain. Clin J Pain. 2009;25(3):218–22.
34. Arnold J., Vercellino G. F., Chiantera V., Schneider A., Mechsner S., Barcena de Arellano M. L. Neuroimmunomodulatory Alterations in Non-Lesional Peritoneum Close to Peritoneal Endometriosis. Neuroimmunomodulation [Internet]. 2013;20(1):9–18. Available from: http://www.karger.com/DOI/10.1159/000342163
35. Rossi F., Bellini G., Torella M., Tortora C., Manzo I., Giordano C., et al. The genetic ablation or pharmacological inhibition of TRPV1 signalling is beneficial for the restoration of quiescent osteoclast activity in ovariectomized mice. Br J Pharmacol. 2014;171(10):2621–30. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009004/
36. Idris A. I., Landao-Bassonga E., Ralston S. H. The TRPV1 ion channel antagonist capsazepine inhibits osteoclast and osteob-last differentiation in vitro and ovariectomy induced bone loss in vivo. Bone. 2016;46(4):1089–99. Available from: http://dx.doi.org/10.1016/j.bone.2010.01.368
38. Cattaruzza F, Spreadbury I, Miranda-Morales M, Grady EF, Vanner S, Bunnett NW. Transient receptor potential ankyrin-1 has a major role in mediating visceral pain in mice. Am J Physiol Gastrointest Liver Physiol. 2009/10/29. 2010 Jan;298(1):G81–91. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19875705