{"paper_id":"3b62e36c-940b-45d3-862c-133cec4e66f1","body_text":"Published online by Cambridge University Press: 05 September 2022\nEndometriosis is a chronic inflammatory disease with pelvic pain and uncharacteristic accompanying symptoms. Endometriosis-associated pain often persists despite treatment of the disease, thus it brings a deleterious impact on their personal lives as well as imposing a substantial economic burden on them. At present, mechanisms underlie endometriosis-associated pain including inflammatory reaction, injury, aberrant blood vessels and the morphological and functional anomaly of the peripheral and central nervous systems. The nerve endings are influenced by the physical and chemical factors surrounding the lesion, via afferent nerve to the posterior root of the spinal nerve, then to the specific cerebral cortex involved in nociception. However, our understanding of the aetiology and mechanism of this complex pain process caused by endometriosis remains incomplete. Identifying the pathogenesis of endometriosis is crucial to disease management, offering proper treatment, and helping patients to seek novel targets for the maintenance and contributors of chronic pain. The main aim of this review is to focus on every possible mechanism of pain related to endometriosis in both peripheral and central nervous systems, and to present related mechanisms of action from the interaction between peripheral lesions and nerves to the changes in transmission of pain, resulting in hyperalgesia and the corresponding alterations in cerebral cortex and brain metabolism.\n- Type\n- Review\n- Information\n- Copyright\n- Copyright © The Author(s), 2022. Published by Cambridge University Press\nChapron, C et al. (2019) Rethinking mechanisms, diagnosis and management of endometriosis. Nature Reviews. Endocrinology 15, 666–682.CrossRefGoogle ScholarPubMed\nShafrir, AL et al. (2018) Risk for and consequences of endometriosis: a critical epidemiologic review. Best Practice & Research. Clinical Obstetrics & Gynaecology 51, 1–15.CrossRefGoogle ScholarPubMed\nPascoal, E et al. (2022) Strengths and limitations of diagnostic tools for endometriosis and relevance in diagnostic test accuracy research. Ultrasound in Obstetrics & Gynecology 60(3), 309–327.CrossRefGoogle ScholarPubMed\nZondervan, KT, Becker, CM and Missmer, SA (2020) Endometriosis. New England Journal of Medicine 382, 1244–1256.CrossRefGoogle ScholarPubMed\nLamvu, G et al. (2021) Chronic pelvic pain in women: a review. JAMA 325, 2381–2391.CrossRefGoogle ScholarPubMed\nWang, Y, Nicholes, K and Shih, IM (2020) The origin and pathogenesis of endometriosis. Annual Review of Pathology 15, 71–95.CrossRefGoogle ScholarPubMed\nLeone Roberti Maggiore, U et al. (2017) Bladder endometriosis: a systematic review of pathogenesis, diagnosis, treatment, impact on fertility, and risk of malignant transformation. European Urology 71, 790–807.CrossRefGoogle ScholarPubMed\nBecker, CM et al. (2022) ESHRE guideline: endometriosis. Human Reproduction Open 2022, hoac009.CrossRefGoogle ScholarPubMed\nTaylor, HS, Kotlyar, AM and Flores, VA (2021) Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet 397, 839–852.CrossRefGoogle ScholarPubMed\nMaddern, J et al. (2020) Pain in endometriosis. Frontiers in Cellular Neuroscience 14, 590823.CrossRefGoogle ScholarPubMed\nLiang, Y et al. (2018) Villainous role of estrogen in macrophage-nerve interaction in endometriosis. Reproductive Biology and Endocrinology: RB&E 16, 122.CrossRefGoogle ScholarPubMed\nGomes, FIF, Cunha, FQ and Cunha, TM (2020) Peripheral nitric oxide signaling directly blocks inflammatory pain. Biochemical Pharmacology 176, 113862.CrossRefGoogle ScholarPubMed\nFassbender, A et al. (2013) Biomarkers of endometriosis. Fertility and Sterility 99, 1135–1145.CrossRefGoogle ScholarPubMed\nWang, G et al. (2009) Rich innervation of deep infiltrating endometriosis. Human Reproduction 24, 827–834.CrossRefGoogle ScholarPubMed\nBokor, A et al. (2009) Density of small diameter sensory nerve fibres in endometrium: a semi-invasive diagnostic test for minimal to mild endometriosis. Human Reproduction 24, 3025–3032.CrossRefGoogle ScholarPubMed\nWang, G et al. (2010) Neuroendocrine cells in eutopic endometrium of women with endometriosis. Human Reproduction 25, 387–391.CrossRefGoogle ScholarPubMed\nTerkelsen, AJ et al. (2017) The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. The Lancet. Neurology 16, 934–944.CrossRefGoogle ScholarPubMed\nLiang, Y et al. (2018) Perineural invasion in endometriotic lesions contributes to endometriosis-associated pain. Journal of Pain Research 11, 1999–2009.CrossRefGoogle ScholarPubMed\nMcAllister, SL, Dmitrieva, N and Berkley, KJ (2012) Sprouted innervation into uterine transplants contributes to the development of hyperalgesia in a rat model of endometriosis. PLoS ONE 7, e31758.CrossRefGoogle Scholar\nTejada, MA et al. (2022) Identification of altered evoked and non-evoked responses in a heterologous mouse model of endometriosis-associated pain. Biomedicines 10, 501–515.CrossRefGoogle Scholar\nTokushige, N et al. (2006) High density of small nerve fibres in the functional layer of the endometrium in women with endometriosis. Human Reproduction 21, 782–787.CrossRefGoogle ScholarPubMed\nEllett, L et al. (2015) Are endometrial nerve fibres unique to endometriosis? A prospective case-control study of endometrial biopsy as a diagnostic test for endometriosis in women with pelvic pain. Human Reproduction 30, 2808–2815.Google ScholarPubMed\nMay, KE et al. (2011) Endometrial alterations in endometriosis: a systematic review of putative biomarkers. Human Reproduction Update 17, 637–653.CrossRefGoogle ScholarPubMed\nZomer, MT et al. (2022) Assessment of nerve fiber density and expression of hormonal receptors within rectosigmoid endometriosis nodules. Journal of Minimally Invasive Gynecology 29, 265–273.CrossRefGoogle ScholarPubMed\nScheerer, C et al. (2017) Reduced sympathetic innervation in endometriosis is associated to semaphorin 3C and 3F expression. Molecular Neurobiology 54, 5131–5141.CrossRefGoogle ScholarPubMed\nBarcena de Arellano, ML and Mechsner, S (2014) The peritoneum – an important factor for pathogenesis and pain generation in endometriosis. Journal of Molecular Medicine 92, 595–602.Google ScholarPubMed\nYilmaz, BD and Bulun, SE (2019) Endometriosis and nuclear receptors. Human Reproduction Update 25, 473–485.CrossRefGoogle ScholarPubMed\nJana, B et al. (2018) Long-term estradiol-17β exposure decreases the cholinergic innervation pattern of the pig ovary. Annals of Anatomy 216, 135–141.CrossRefGoogle ScholarPubMed\nGhersa, F et al. (2019) Reduced inflammatory state promotes reinnervation of endometriotic-like lesions in TNFRp55 deficient mice. Molecular Human Reproduction 25, 385–396.CrossRefGoogle ScholarPubMed\nBenitez, A et al. (2021) Nerve growth factor: a dual activator of noradrenergic and cholinergic systems of the rat ovary. Frontiers in Endocrinology 12, 636600.CrossRefGoogle ScholarPubMed\nHao, M et al. (2021) Reduced vagal tone in women with endometriosis and auricular vagus nerve stimulation as a potential therapeutic approach. Scientific Reports 11, 1345.CrossRefGoogle ScholarPubMed\nYeater, TD et al. (2021) Chronic pain is associated with reduced sympathetic nervous system reactivity during simple and complex walking tasks: potential cerebral mechanisms. Chronic Stress 5, 24705470211030273.CrossRefGoogle ScholarPubMed\nFerrero, S et al. (2010) Loss of sympathetic nerve fibers in intestinal endometriosis. Fertility and Sterility 94, 2817–2819.CrossRefGoogle ScholarPubMed\nLaschke, MW and Menger, MD (2018) Basic mechanisms of vascularization in endometriosis and their clinical implications. Human Reproduction Update 24, 207–224.CrossRefGoogle ScholarPubMed\nBouquet de Joliniere, J et al. (2021) Antiangiogenic therapy as a new strategy in the treatment of endometriosis? The first case report. Frontiers in Surgery 8, 791686.CrossRefGoogle ScholarPubMed\nApte, RS, Chen, DS and Ferrara, N (2019) VEGF in signaling and disease: beyond discovery and development. Cell 176, 1248–1264.CrossRefGoogle ScholarPubMed\nZhang, F et al. (2018) Expression of MMIF, HIF-1α and VEGF in serum and endometrial tissues of patients with endometriosis. Current Medical Science 38, 499–504.CrossRefGoogle ScholarPubMed\nHsiao, KY et al. (2015) Pathological functions of hypoxia in endometriosis. Frontiers in Bioscience 7, 352–366.CrossRefGoogle ScholarPubMed\nYoung, VJ et al. (2017) The role of TGF-β in the pathophysiology of peritoneal endometriosis. Human Reproduction Update 23, 548–559.CrossRefGoogle ScholarPubMed\nRashidi, BH et al. (2019) Association of vascular endothelial growth factor (VEGF) gene polymorphisms and expression with the risk of endometriosis: a case-control study. Molecular Biology Reports 46, 3445–3450.CrossRefGoogle ScholarPubMed\nZhou, J et al. (2020) Peritoneal fluid cytokines reveal new insights of endometriosis subphenotypes. International Journal of Molecular Sciences 21, 3515.CrossRefGoogle ScholarPubMed\nPerricos, A et al. (2020) Does the use of the ‘Proseek(®) multiplex oncology I panel’ on peritoneal fluid allow a better insight in the pathophysiology of endometriosis, and in particular deep-infiltrating endometriosis?. Journal of Clinical Medicine 9, 2009.CrossRefGoogle Scholar\nFahey, E and Doyle, SL (2019) IL-1 family cytokine regulation of vascular permeability and angiogenesis. Frontiers in Immunology 10, 1426.CrossRefGoogle ScholarPubMed\nRaimondo, D et al. (2020) Rectosigmoid endometriosis vascular patterns at intraoperative indocyanine green angiography and their correlation with clinicopathological data. Surgical Innovation 27, 474–480.CrossRefGoogle ScholarPubMed\nTurco, LC et al. (2021) Near-infrared imaging with indocyanine green for the treatment of endometriosis: results from the Gre-endo trial. Frontiers in Oncology 11, 737938.CrossRefGoogle ScholarPubMed\nCohen, SP, Vase, L and Hooten, WM (2021) Chronic pain: an update on burden, best practices, and new advances. Lancet 397, 2082–2097.CrossRefGoogle ScholarPubMed\nChang, CT, Jiang, BY and Chen, CC (2019) Ion channels involved in substance P-mediated nociception and antinociception. International Journal of Molecular Sciences 20, 1596.CrossRefGoogle ScholarPubMed\nLin, FY et al. (2021) The clinical application of pulsed radiofrequency induces inflammatory pain via MAPKs activation: a novel hint for pulsed radiofrequency treatment. International Journal of Molecular Sciences 22, 11865.CrossRefGoogle ScholarPubMed\nCampbell, JN and Meyer, RA (2006) Mechanisms of neuropathic pain. Neuron 52, 77–92.CrossRefGoogle ScholarPubMed\nCoxon, L, Wiech, K and Vincent, K (2021) Is there a neuropathic-like component to endometriosis-associated pain? Results from a large cohort questionnaire study. Frontiers in Pain Research 2, 743812.CrossRefGoogle Scholar\nLevine, JD, Fields, HL and Basbaum, AI (1993) Peptides and the primary afferent nociceptor. Journal of Neuroscience 13, 2273–2286.CrossRefGoogle ScholarPubMed\nTracey, I and Dickenson, A (2012) SnapShot: pain perception. Cell 148, 1308–1308, e2.CrossRefGoogle ScholarPubMed\nSadeghi, M et al. (2018) Contribution of membrane receptor signalling to chronic visceral pain. International Journal of Biochemistry & Cell Biology 98, 10–23.CrossRefGoogle ScholarPubMed\nNanda, A et al. (2020) Cytokines, angiogenesis, and extracellular matrix degradation are augmented by oxidative stress in endometriosis. Annals of Laboratory Medicine 40, 390–397.CrossRefGoogle ScholarPubMed\nGueuvoghlanian-Silva, BY et al. (2018) Treg and NK cells related cytokines are associated with deep rectosigmoid endometriosis and clinical symptoms related to the disease. Journal of Reproductive Immunology 126, 32–38.CrossRefGoogle ScholarPubMed\nSoni, UK et al. (2019) A high level of TGF-β1 promotes endometriosis development via cell migration, adhesiveness, colonization, and invasiveness. Biology of Reproduction 100, 917–938.CrossRefGoogle Scholar\nZhang, J et al. (2017) TGF-β1 suppresses CCL3/4 expression through the ERK signaling pathway and inhibits intervertebral disc degeneration and inflammation-related pain in a rat model. Experimental and Molecular Medicine 49, e379.CrossRefGoogle ScholarPubMed\nYu, J et al. (2018) IL-1β stimulates brain-derived neurotrophic factor production in eutopic endometriosis stromal cell cultures: a model for cytokine regulation of neuroangiogenesis. American Journal of Pathology 188, 2281–2292.CrossRefGoogle Scholar\nMa, W, Li, L and Xing, S (2019) PGE2/EP4 receptor and TRPV1 channel are involved in repeated restraint stress-induced prolongation of sensitization pain evoked by subsequent PGE2 challenge. Brain Research 1721, 146335.CrossRefGoogle ScholarPubMed\nCho, S et al. (2010) Expression of cyclooxygenase-2 in eutopic endometrium and ovarian endometriotic tissue in women with severe endometriosis. Gynecologic and Obstetric Investigation 69, 93–100.CrossRefGoogle ScholarPubMed\nMulet, M et al. (2017) Early increased density of cyclooxygenase-2 (COX-2) immunoreactive neurons in down syndrome. Folia Neuropathologica 55, 154–160.CrossRefGoogle ScholarPubMed\nScutiero, G et al. (2017) Oxidative stress and endometriosis: a systematic review of the literature. Oxidative Medicine and Cellular Longevity 2017, 7265238.CrossRefGoogle ScholarPubMed\nSantulli, P et al. (2015) Protein oxidative stress markers in peritoneal fluids of women with deep infiltrating endometriosis are increased. Human Reproduction 30, 49–60.CrossRefGoogle ScholarPubMed\nBulun, SE (2009) Endometriosis. New England Journal of Medicine 360, 268–279.CrossRefGoogle ScholarPubMed\nMa, J et al. (2021) Single-cell transcriptomic analysis of endometriosis provides insights into fibroblast fates and immune cell heterogeneity. Cell & Bioscience 11, 125.CrossRefGoogle ScholarPubMed\nHey-Cunningham, AJ et al. (2021) Comprehensive analysis utilizing flow cytometry and immunohistochemistry reveals inflammatory changes in local endometrial and systemic dendritic cell populations in endometriosis. Human Reproduction 36, 415–428.CrossRefGoogle ScholarPubMed\nWu, J et al. (2017) Macrophage and nerve interaction in endometriosis. Journal of Neuroinflammation 14, 53.CrossRefGoogle ScholarPubMed\nMalet, M and Brumovsky, PR (2015) VGLUTs and glutamate synthesis-focus on DRG neurons and pain. Biomolecules 5, 3416–3437.CrossRefGoogle ScholarPubMed\nNoh, ASM and Ismail, CAN (2020) A review on chronic pain in rheumatoid arthritis: a focus on activation of NR2B subunit of N-methyl-d-aspartate receptors. The Malaysian Journal of Medical Sciences 27, 6–21.Google ScholarPubMed\nForster, R et al. (2019) Macrophage-derived insulin-like growth factor-1 is a key neurotrophic and nerve-sensitizing factor in pain associated with endometriosis. FASEB Journal 33, 11210–11222.CrossRefGoogle ScholarPubMed\nAich, A, Afrin, LB and Gupta, K (2015) Mast cell-mediated mechanisms of nociception. International Journal of Molecular Sciences 16, 29069–29092.CrossRefGoogle ScholarPubMed\nBorelli, V et al. (2019) Mast cells in peritoneal fluid from women with endometriosis and their possible role in modulating sperm function. Frontiers in Physiology 10, 1543.CrossRefGoogle ScholarPubMed\nGenovese, T et al. (2022) Molecular and biochemical mechanism of cannabidiol in the management of the inflammatory and oxidative processes associated with endometriosis. International Journal of Molecular Sciences 23, 5427.CrossRefGoogle ScholarPubMed\nSikora, J et al. (2018) The role of complement components C1q, MBL and C1 inhibitor in pathogenesis of endometriosis. Archives of Gynecology and Obstetrics 297, 1495–1501.CrossRefGoogle ScholarPubMed\nAgostinis, C et al. (2020) Immunological basis of the endometriosis: the complement system as a potential therapeutic target. Frontiers in Immunology 11, 599117.CrossRefGoogle ScholarPubMed\nAgostinis, C et al. (2020) Complement Component 3 expressed by the endometrial ectopic tissue is involved in the endometriotic lesion formation through mast cell activation. bioRxiv, 2020.11.19.389536.Google Scholar\nGrammatis, AL, Georgiou, EX and Becker, CM (2021) Pentoxifylline for the treatment of endometriosis-associated pain and infertility. The Cochrane Database of Systematic Reviews 8, Cd007677.Google ScholarPubMed\nGołąbek, A, Kowalska, K and Olejnik, A (2021) Polyphenols as a diet therapy concept for endometriosis – current opinion and future perspectives. Nutrients 13, 1347.CrossRefGoogle ScholarPubMed\nSun, LH et al. (2019) Estrogen modulation of visceral pain. Journal of Zhejiang University. Science B 20, 628–636.CrossRefGoogle ScholarPubMed\nHu, Z, Mamillapalli, R and Taylor, HS (2019) Increased circulating miR-370-3p regulates steroidogenic factor 1 in endometriosis. American Journal of Physiology. Endocrinology and Metabolism 316, E373–Ee82.CrossRefGoogle ScholarPubMed\nGonçalves, RM et al. (2021) COX-2 promotes mammary adipose tissue inflammation, local estrogen biosynthesis, and carcinogenesis in high-sugar/fat diet treated mice. Cancer Letters 502, 44–57.CrossRefGoogle ScholarPubMed\nFerrari, LF, Araldi, D and Levine, JD (2017) Regulation of expression of hyperalgesic priming by estrogen receptor α in the rat. The Journal of Pain 18, 574–582.CrossRefGoogle ScholarPubMed\nLatini, C et al. (2008) Remodeling of uterine innervation. Cell and Tissue Research 334, 1–6.CrossRefGoogle ScholarPubMed\nDzieran, J et al. (2018) MYCN-amplified neuroblastoma maintains an aggressive and undifferentiated phenotype by deregulation of estrogen and NGF signaling. Proceedings of the National Academy of Sciences of the USA 115, E1229–E1e38.CrossRefGoogle ScholarPubMed\nGreaves, E et al. (2014) Estrogen receptor (ER) agonists differentially regulate neuroangiogenesis in peritoneal endometriosis via the repellent factor SLIT3. Endocrinology 155, 4015–4026.CrossRefGoogle ScholarPubMed\nCao, DY et al. (2012) Estrogen receptor β activation is antinociceptive in a model of visceral pain in the rat. The Journal of Pain 13, 685–694.CrossRefGoogle Scholar\nZhang, W et al. (2020) Estrogen modulation of pain perception with a novel 17β-estradiol pretreatment regime in ovariectomized rats. Biology of Sex Differences 11, 2.CrossRefGoogle ScholarPubMed\nArosh, JA, Lee, J and Banu, SK (2022) Effects of dual inhibition of AKT and ERK1/2 pathways on endometrial pro-inflammatory, hormonal, and epigenetic microenvironment in endometriosis. Molecular and Cellular Endocrinology 539, 111446.CrossRefGoogle ScholarPubMed\nOrtíz-Rentería, M et al. (2018) TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain. Proceedings of the National Academy of Sciences of the USA 115, E1657–E1e66.CrossRefGoogle ScholarPubMed\nvan Aken, M et al. (2018) Hair cortisol and the relationship with chronic pain and quality of life in endometriosis patients. Psychoneuroendocrinology 89, 216–222.CrossRefGoogle ScholarPubMed\nOrtiz, R et al. (2020) Hypothalamic–pituitary–adrenal axis responses in women with endometriosis-related chronic pelvic pain. Reproductive Sciences 27, 1839–1847.CrossRefGoogle ScholarPubMed\nvan den Beukel, BA et al. (2017) Surgical treatment of adhesion-related chronic abdominal and pelvic pain after gynaecological and general surgery: a systematic review and meta-analysis. Human Reproduction Update 23, 276–288.Google ScholarPubMed\nAnaf, V et al. (2000) Relationship between endometriotic foci and nerves in rectovaginal endometriotic nodules. Human Reproduction 15, 1744–1750.CrossRefGoogle ScholarPubMed\nKalkan, Ü and Daniilidis, A (2019) Laparoscopic diagnosis and treatment of obturator nerve entrapment because of a deep infiltrating endometriotic nodule: a case report. Journal of Minimally Invasive Gynecology 26, 766–769.CrossRefGoogle ScholarPubMed\nKale, A et al. (2022) Comparison of isolated sciatic nerve and sacral nerve root endometriosis: a review of the literature. Journal of Minimally Invasive Gynecology 29, 943–951.CrossRefGoogle ScholarPubMed\nLiu, Z et al. (2018) Fractalkine/CX3CR1 contributes to endometriosis-induced neuropathic pain and mechanical hypersensitivity in rats. Frontiers in Cellular Neuroscience 12, 495.CrossRefGoogle ScholarPubMed\nKamboj, AK, Hoversten, P and Oxentenko, AS (2019) Chronic abdominal wall pain: a common yet overlooked etiology of chronic abdominal pain. Mayo Clinic Proceedings 94, 139–144.CrossRefGoogle ScholarPubMed\nFarag, S et al. (2018) Management, prevention, and sequelae of adhesions in women undergoing laparoscopic gynecologic surgery: a systematic review. Journal of Minimally Invasive Gynecology 25, 1194–1216.CrossRefGoogle ScholarPubMed\nGrundy, L, Erickson, A and Brierley, SM (2019) Visceral pain. Annual Review of Physiology 81, 261–284.CrossRefGoogle ScholarPubMed\nBasbaum, AI et al. (2009) Cellular and molecular mechanisms of pain. Cell 139, 267–284.CrossRefGoogle ScholarPubMed\nHayashi, S et al. (2020) Novel ovarian endometriosis model causes infertility via iron-mediated oxidative stress in mice. Redox Biology 37, 101726.CrossRefGoogle ScholarPubMed\nMaatuf, Y, Geron, M and Priel, A (2019) The role of toxins in the pursuit for novel analgesics. Toxins (Basel) 11, 131.CrossRefGoogle ScholarPubMed\nFinnerup, NB, Kuner, R and Jensen, TS (2021) Neuropathic pain: from mechanisms to treatment. Physiological Reviews 101, 259–301.CrossRefGoogle ScholarPubMed\nHoffman, D (2015) Central and peripheral pain generators in women with chronic pelvic pain: patient centered assessment and treatment. Current Rheumatology Reviews 11, 146–166.CrossRefGoogle ScholarPubMed\nPhan, VT et al. (2021) Widespread myofascial dysfunction and sensitisation in women with endometriosis-associated chronic pelvic pain: a cross-sectional study. European Journal of Pain 25, 831–840.CrossRefGoogle ScholarPubMed\nGruber, TM and Mechsner, S (2021) Pathogenesis of endometriosis: the origin of pain and subfertility. Cells 10, 1381.CrossRefGoogle ScholarPubMed\nLopes, DM, Denk, F and McMahon, SB (2017) The molecular fingerprint of dorsal root and trigeminal ganglion neurons. Frontiers in Molecular Neuroscience 10, 304.CrossRefGoogle ScholarPubMed\nHucho, T and Levine, JD (2007) Signaling pathways in sensitization: toward a nociceptor cell biology. Neuron 55, 365–376.CrossRefGoogle Scholar\nAbbas, MA (2020) Modulation of TRPV1 channel function by natural products in the treatment of pain. Chemico-Biological Interactions 330, 109178.CrossRefGoogle ScholarPubMed\nBohonyi, N et al. (2017) Local upregulation of transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1 ion channels in rectosigmoid deep infiltrating endometriosis. Molecular Pain 13, 1744806917705564.CrossRefGoogle ScholarPubMed\nFattori, V et al. (2020) Nonsurgical mouse model of endometriosis-associated pain that responds to clinically active drugs. Pain 161, 1321–1331.CrossRefGoogle ScholarPubMed\nMcAllister, SL et al. (2021) Aberrant reactive aldehyde detoxification by aldehyde dehydrogenase-2 influences endometriosis development and pain-associated behaviors. Pain 162, 71–83.CrossRefGoogle ScholarPubMed\nTrapero, C et al. (2019) Impaired expression of ectonucleotidases in ectopic and eutopic endometrial tissue is in favor of ATP accumulation in the tissue microenvironment in endometriosis. International Journal of Molecular Sciences 20, 5532.CrossRefGoogle ScholarPubMed\nOrr, MB and Gensel, JC (2018) Spinal cord injury scarring and inflammation: therapies targeting glial and inflammatory responses. Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics 15, 541–553.CrossRefGoogle ScholarPubMed\nKwon, SG et al. (2014) Blockade of peripheral P2Y1 receptors prevents the induction of thermal hyperalgesia via modulation of TRPV1 expression in carrageenan-induced inflammatory pain rats: involvement of p38 MAPK phosphorylation in DRGs. Neuropharmacology 79, 368–379.CrossRefGoogle ScholarPubMed\nTrapero, C and Martín-Satué, M (2020) Purinergic signaling in endometriosis-associated pain. International Journal of Molecular Sciences 21, 8512.CrossRefGoogle ScholarPubMed\nDing, S et al. (2020) Activation of ATF3/AP-1 signaling pathway is required for P2X3-induced endometriosis pain. Human Reproduction 35, 1130–1144.CrossRefGoogle ScholarPubMed\nXiang, X et al. (2019) Electroacupuncture stimulation alleviates CFA-induced inflammatory pain via suppressing P2X3 expression. International Journal of Molecular Sciences 20, 3248.CrossRefGoogle ScholarPubMed\nGreaves, E et al. (2014) Elevated peritoneal expression and estrogen regulation of nociceptive ion channels in endometriosis. Journal of Clinical Endocrinology and Metabolism 99, E1738–E1743.CrossRefGoogle ScholarPubMed\nGreaves, E et al. (2017) EP(2) receptor antagonism reduces peripheral and central hyperalgesia in a preclinical mouse model of endometriosis. Scientific Reports 7, 44169.CrossRefGoogle Scholar\nZhou, YM et al. (2019) Enhancement of acid-sensing ion channel activity by prostaglandin E2 in rat dorsal root ganglion neurons. Brain Research 1724, 146442.CrossRefGoogle ScholarPubMed\nRiemma, G et al. (2020) Ion channels in the pathogenesis of endometriosis: a cutting-edge point of view. International Journal of Molecular Sciences 21, 1114.CrossRefGoogle ScholarPubMed\nMaulitz, L et al. (2022) Endometriosis, psychiatric comorbidities and neuroimaging: estimating the odds of an endometriosis brain. Frontiers in Neuroendocrinology 65, 100988.CrossRefGoogle ScholarPubMed\nYang, S and Chang, MC (2019) Chronic pain: structural and functional changes in brain structures and associated negative affective states. International Journal of Molecular Sciences 20, 3130.CrossRefGoogle ScholarPubMed\nTu, CH et al. (2013) Menstrual pain is associated with rapid structural alterations in the brain. Pain 154, 1718–1724.CrossRefGoogle Scholar\nVincent, K et al. (2011) Dysmenorrhoea is associated with central changes in otherwise healthy women. Pain 152, 1966–1975.CrossRefGoogle ScholarPubMed\nAs-Sanie, S et al. (2012) Changes in regional gray matter volume in women with chronic pelvic pain: a voxel-based morphometry study. Pain 153, 1006–1014.CrossRefGoogle ScholarPubMed\nMatsuo, Y et al. (2017) Attenuation of cortical activity triggering descending pain inhibition in chronic low back pain patients: a functional magnetic resonance imaging study. Journal of Anesthesia 31, 523–530.CrossRefGoogle ScholarPubMed\nKang, D et al. (2019) What does the grey matter decrease in the medial prefrontal cortex reflect in people with chronic pain? European Journal of Pain 23, 203–219.CrossRefGoogle ScholarPubMed\nFerdek, MA et al. (2019) Effective connectivity of beta oscillations in endometriosis-related chronic pain during rest and pain-related mental imagery. The Journal of Pain 20, 1446–1458.CrossRefGoogle ScholarPubMed\nAs-Sanie, S et al. (2016) Functional connectivity is associated with altered brain chemistry in women with endometriosis-associated chronic pelvic pain. The Journal of Pain 17, 1–13.CrossRefGoogle ScholarPubMed\nOng, WY, Stohler, CS and Herr, DR (2019) Role of the prefrontal cortex in pain processing. Molecular Neurobiology 56, 1137–1166.CrossRefGoogle ScholarPubMed\nDuncan, NW et al. (2013) Glutamate concentration in the medial prefrontal cortex predicts resting-state cortical-subcortical functional connectivity in humans. PLoS ONE 8, e60312.CrossRefGoogle ScholarPubMed\nHuang, J et al. (2019) A neuronal circuit for activating descending modulation of neuropathic pain. Nature Neuroscience 22, 1659–1668.CrossRefGoogle ScholarPubMed\nCortés-Montero, E et al. (2020) Calmodulin supports TRPA1 channel association with opioid receptors and glutamate NMDA receptors in the nervous tissue. International Journal of Molecular Sciences 22, 229.CrossRefGoogle ScholarPubMed\nTorres-Reverón, A et al. (2016) Endometriosis is associated with a shift in MU opioid and NMDA receptor expression in the brain periaqueductal gray. Reproductive Sciences 23, 1158–1167.CrossRefGoogle ScholarPubMed\nBrawn, J et al. (2014) Central changes associated with chronic pelvic pain and endometriosis. Human Reproduction Update 20, 737–747.CrossRefGoogle ScholarPubMed\nYano, M et al. (2019) Pain-related behavior and brain activation in cynomolgus macaques with naturally occurring endometriosis. Human Reproduction 34, 469–478.CrossRefGoogle ScholarPubMed\nColvin, LA, Bull, F and Hales, TG (2019) Perioperative opioid analgesia-when is enough too much? A review of opioid-induced tolerance and hyperalgesia. Lancet 393, 1558–1568.CrossRefGoogle Scholar\nBuehlmann, D et al. (2019) Prospective administration of anti-nerve growth factor treatment effectively suppresses functional connectivity alterations after cancer-induced bone pain in mice. Pain 160, 151–159.CrossRefGoogle ScholarPubMed\nUmbrain, V et al. (2008) Intrathecal lidocaine elevates prostaglandin E2 levels in cerebrospinal fluid: a microdialysis study in freely moving rats. British Journal of Anaesthesia 101, 716–722.CrossRefGoogle ScholarPubMed\nZheng, P et al. (2019) Evaluation of the brain functional activities in rats various location-endometriosis pain model. Annals of Translational Medicine 7, 767.CrossRefGoogle ScholarPubMed\nWimmer, GE and Büchel, C (2021) Reactivation of single-episode pain patterns in the hippocampus and decision making. Journal of Neuroscience 41, 7894–7908.CrossRefGoogle ScholarPubMed\nLi, T et al. (2018) Endometriosis alters brain electrophysiology, gene expression and increases pain sensitization, anxiety, and depression in female mice. Biology of Reproduction 99, 349–359.CrossRefGoogle ScholarPubMed\nBeissner, F et al. (2018) Psychotherapy with somatosensory stimulation for endometriosis-associated pain: the role of the anterior hippocampus. Biological Psychiatry 84, 734–742.CrossRefGoogle ScholarPubMed\nPadda, J et al. (2021) Depression and its effect on the menstrual cycle. Cureus 13, e16532.Google ScholarPubMed\nHansen, KB et al. (2017) NMDA receptors in the central nervous system. Methods in Molecular Biology 1677, 1–80.CrossRefGoogle ScholarPubMed\nZheng, P et al. (2020) Central sensitization-related changes in brain function activity in a rat endometriosis-associated pain model. Journal of Pain Research 13, 95–107.CrossRefGoogle Scholar\nXu, B et al. (2000) The role of brain-derived neurotrophic factor receptors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving TrkB. Journal of Neuroscience 20, 6888–6897.CrossRefGoogle ScholarPubMed\nCordaro, M et al. (2021) Hidrox(®) and endometriosis: biochemical evaluation of oxidative stress and pain. Antioxidants (Basel) 10, 720.CrossRefGoogle ScholarPubMed\nRostami, J et al. (2021) Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates. Journal of Neuroinflammation 18, 124.CrossRefGoogle ScholarPubMed\nFlores-Bonilla, A et al. (2019) Astrocyte activation is increased in a rat endometriosis model. The FASEB Journal 33, lb619–lb619.CrossRefGoogle Scholar\n- 13\n- Cited by\nCited by\nCrossref Citations\nWatrowski, Rafał\nSchuster, Eva\nVan Gorp, Toon\nHofstetter, Gerda\nFischer, Michael B.\nMahner, Sven\nPolterauer, Stefan\nZeillinger, Robert\nand\nObermayr, Eva\n2024.\nAssociation of the Single Nucleotide Polymorphisms rs11556218, rs4778889, rs4072111, and rs1131445 of the Interleukin-16 Gene with Ovarian Cancer.\nInternational Journal of Molecular Sciences,\nVol. 25,\nIssue. 19,\np.\n10272.\nVastrad, Basavaraj\nand\nVastrad, Chanabasayya\n2024.\nScreening and identification of key biomarkers associated with endometriosis using bioinformatics and next-generation sequencing data analysis.\nEgyptian Journal of Medical Human Genetics,\nVol. 25,\nIssue. 1,\nChen, Danni\nRen, Yunying\nJin, Jing\nLiu, Shuzhen\nZhan, Xiaoxuan\nLi, Xin\nLiang, Ruining\nand\nDing, Zhiling\n2024.\nPingchong Jiangni recipe through nerve growth factor/transient receptor potential vanilloid 1 signaling pathway to relieve pain in endometriosis model rats.\nJournal of Ethnopharmacology,\nVol. 318,\nIssue. ,\np.\n116940.\nFalsetta, Megan L.\nand\nChrysilla, Emanuelle\n2025.\nCurrent Understanding of Endometriosis Pathophysiology and Future Perspectives.\nSeminars in Reproductive Medicine,\nVol. 43,\nIssue. 03,\np.\n167.\nSanei Taheri, Morteza\nBoroujeni, Majid Valiyan\nFouladi, Zahra Mahboubi\nArdebili, Shahla Noori\nChegeni, Samaneh\nMoharamzad, Yashar\nAbniki, Simin\nand\nHasanzadeh, Sara\n2025.\nEvaluation of the relationship between thyroid hormones and endometriosis: a clinical investigation.\nInternational Journal of Reproduction, Contraception, Obstetrics and Gynecology,\nVol. 14,\nIssue. 9,\np.\n2846.\nWang, Jingyi\nand\nWang, Xiaojie\n2025.\nResearch progress on the correlation between microbiota and endometriosis.\nEuropean Journal of Obstetrics & Gynecology and Reproductive Biology,\nVol. 314,\nIssue. ,\np.\n114671.\nWang, Min\nLiu, Wei\nZheng, Lianwen\nMa, Shuai\nJin, Lianhai\nZhao, Donghai\nand\nLi, Dandan\n2025.\nBroadening horizons: microbiota as a novel biomarker and potential treatment for endometriosis.\nFrontiers in Microbiology,\nVol. 16,\nIssue. ,\nTang, Weikang\nLi, Xuan\nLiu, Huixia\nXu, Chunyan\nand\nDeng, Siyao\n2025.\nThe role of macrophages in chronic pain.\nCytokine,\nVol. 185,\nIssue. ,\np.\n156813.\nAlzamora-Schmatz, Maria C.\nand\nGubbels, Ashley\n2025.\nMore than the Lesion: Unraveling the Complexities of Endometriosis-Associated Pain.\nSeminars in Reproductive Medicine,\nVol. 43,\nIssue. 03,\np.\n202.\nBéraud, Bastien Léo\nMeichtry, André\nHanusch, Kay-Uwe\nand\nHilfiker, Roger\n2025.\nLanguage errors in pain medicine: An umbrella review.\nThe Journal of Pain,\nVol. 28,\nIssue. ,\np.\n104738.\nWu, Qiong\nYang, Fan\nYang, Ruyu\nMai, Huaxi\nCai, Heng\nHe, Yushi\nLiu, Qingyin\nMaimaitijiang, Ayituersun\nLan, Xi\nZou, Qiuyu\nWei, Yajing\nHuang, Biqi\nZhang, Chunyu\nYuan, Li\nLiang, Zongwen\nTan, Hao\nDing, Xinyue\nHe, Xiaoru\nJiang, Shaoru\nYao, Shuzhong\nand\nLiang, Yanchun\n2026.\nCX3CR1/P2X4R signaling-mediated spinal microglial M1 polarization contributes to chronic pelvic pain in endometriosis.\nInternational Immunopharmacology,\nVol. 175,\nIssue. ,\np.\n116471.\nWilliams, Auni C.\nMartinez Yus, Marta\nSanthanam, Lakshmi\nand\nAlexander, Lacy M.\n2026.\nAttenuated cyclooxygenase-mediated vasodilation in cutaneous microvasculature with no difference in platelet aggregation in women with endometriosis.\nJournal of Applied Physiology,\nVol. 140,\nIssue. 3,\np.\n652.\nLu, Tianyi\nDeng, Zhengrong\nYang, Kailin\nand\nZhou, Shengtao\n2026.\nCharting the nerve–immune axis in endometriosis.\nTrends in Immunology,","source_license":"CC0","license_restricted":false}