{"paper_id":"fa227c06-c423-4b55-b020-4eb8cbd679b6","body_text":"There are various chronic inflammatory diseases related to the genitourinary tract, such as\ninterstitial cystitis/bladder pain syndrome (IC/BPS) and chronic prostatitis/chronic pelvic\npain syndrome (CP/CPPS). Although these diseases lead to marked deterioration of quality of\nlife (QOL) in patients due to pain or urinary urgency, the pathophysiology of these diseases\nremains unclear. Epidemiological studies have shown that patients with these diseases are\nmore likely to have other chronic illnesses, such as irritable bowel syndrome (IBS) or\nvulvodynia, in comparison with the general population ( 1 ,  2 ). Pelvic organ cross-sensitization is\nconsidered to be one of the factors contributing to these relationships ( 3 ). It is known that afferent neural pathways innervating\npelvic organs converge in the central nervous system. Cross-sensitization implies\ntransmission of noxious stimuli from a diseased pelvic organ to an adjacent normal\nstructure, resulting in functional changes in the latter. Cross-sensitization in the pelvis\nmainly occurs via shared sensory neural pathways at the prespinal, spinal, and supraspinal\nlevels ( 4 ). The aim of this paper is to review the\npathophysiology of chronic diseases related to the genitourinary tract in terms of pelvic\norgan cross-sensitization.\nIC/BPS is a chronic pain syndrome, the symptoms of which include urinary frequency,\nurinary urgency, and pain ( 5 ). According to an\nepidemiological study, the hazard ratio for developing IC/BPS in subjects with\nendometriosis compared to subjects without endometriosis was 4.43 (95% confidence interval\n(CI): 2.13–9.23) ( 6 ). In addition, another study\nshowed that patients with interstitial cystitis were more likely to be diagnosed with IBS\n(odds ratio (OR) 11; 95% CI 2.7–52) ( 7 ). Several\nbasic laboratory studies have shown that pelvic organ cross-sensitization plays a role in\nthe clinically overlapping symptoms of these diseases. For example, it has been shown in\nrats that surgical induction of endometriosis significantly reduced micturition thresholds\nand increased bladder inflammation ( 8 ). Moreover,\nthere have been reports showing pelvic organ cross-sensitization between experimental\ncolitis-induced bladder overactivity and painful bladder sensations ( 9 ,  10 ). We investigated whether\nmicroglia in the spinal cord contributed to central sensitization in experimental colitis\nin rats ( 9 ). In our study, rats with experimental\ncolitis showed bladder overactivity and increased pain bladder sensations. Additionally,\nthe number of spinal microglia was significantly larger in these rats than that in the\ncontrol rats. Inhibition of spinal microglia significantly recovered these changes in\nbladder hyperexcitability caused by experimental colitis ( 9 ). These results imply that microglia may play a role in the colon-to-bladder\nneural cross-talk, at the level of the spinal cord, in a rat model of colitis.\nFurthermore, another study indicated that experimental colitis led to bladder\nhypersensitivity via pelvic organ cross-sensitization between the colon and bladder, which\nwas attributed to the activation of dichotomized afferent neurons innervating both organs,\nat the level of the dorsal root ganglia (DRG) ( 10 ).\nThus, it may be assumed that activation of the spinal microglia and/or afferent neurons in\nthe DRG is one of the underlying mechanisms in pelvic organ cross-sensitization between\nthe bladder and colon or between the bladder and uterus. It is possible that these\npathophysiologies could contribute to the overlapping symptoms in patients with\nIC/BPS.\nCP/CPPS is defined when pelvic pain is present for ≥3 of the preceding 6 months, and no\nother identifiable causes have been detected. Other symptoms include obstructive or\nirritative voiding difficulties, ejaculatory pain, and sexual dysfunction. Men affected by\nCP/CPPS have significantly decreased QOL ( 11 ). A\nclinical study showed that Hunner-type IC is a common comorbidity among patients with\nrefractory CP/CPPS ( 12 ). Several basic studies have\nshown that pelvic organ cross-sensitization plays a role in the clinically overlapping\nsymptoms of these diseases ( 13 ,  14 ). A basic study in rats demonstrated that\nexperimental prostatitis caused detrusor overactivity ( 13 ). In addition, it was reported that in rats a significant number of DRG\nneurons with dichotomized afferents innervate both the prostate and bladder ( 13 ). In rats with prostatic inflammation, the\npopulations of transient receptor potential vanilloid 1, transient receptor potential\nankyrin 1, and P2X2 receptors increased due to mRNA activity in the bladder afferent and\ndouble-labeled neurons compared with the non-labeled neurons ( 13 ). This study concluded that prostate-to-bladder cross-sensitization\nthrough the primary afferent pathways, which contain dichotomized afferents, could be an\nimportant mechanism contributing to bladder overactivity and afferent hyperexcitability\ninduced by prostatic inflammation ( 13 ). Therefore,\nit is possible that pelvic organ cross-sensitization is one of the underlying\npathophysiologies of CP/CPPS.\nIt is known that exposure to low temperature tends to cause lower urinary tract symptoms,\nsuch as urgency and urinary frequency in patients with overactive bladder ( 15 ). According to animal studies, cross-sensitization\nbetween the skin and bladder was associated with this phenomenon ( 16 ,  17 ). Localized cooling of\nthe skin evoked rapid bladder contractions and voids in anesthetized mice. These responses\nwere strongly attenuated in transient receptor potential melastatin 8 (TRPM8) knockout\nmice ( 16 ). In addition, another study indicated\nthat spraying TRPM8 channel agonist onto the skin induced detrusor overactivity in rats\n( 17 ). In this study, the authors speculated that\nskin to bladder cross-sensitization through TRPM8 channels on the skin may be mediated by\nthe nervous system, including either spinal tract neurons or via the pontine micturition\ncenter.\n\nAs reviewed in this paper, organ cross-sensitization could be associated with the\npathophysiology of several chronic diseases related to the genitourinary tract, such as\nIC/BPS and CP/CPPS. Since there are few treatments to cure these diseases completely,\nfurther studies regarding organ cross-sensitization may provide new insights into the\npathophysiology and treatment strategies for these diseases.\n\nWe have no conflicts of interest to declare.","source_license":"CC0","license_restricted":false}