Overactive bladder syndrome (OAB) and interstitial cystitis/painful bladder syndrome (IC/PBS) are common, chronic, pelvic disorders affecting approximately ∼16% of the western population (Hanno, 2002; Irwin et al., 2006; McLennan, 2014; Truzzi et al., 2016). Urgency, frequency, and nocturia are common symptoms of both OAB and IC. However, these conditions may be differentiated by the presence of urge urinary incontinence in patients with OAB and pelvic pain in IC patients (MacDiarmid and Sand, 2007; Hanno and Dmochowski, 2009; Haylen et al., 2010; Homma et al., 2016). As both of these disorders are diagnosed in the absence of bacterial infection or obvious pathology, the etiology of OAB and IC/PBS symptoms remain unknown. Accordingly, efficacious therapeutic options are limited, contributing to the significant societal and economic impact of greater than $70 billion per annum in the United States (Pierce and Christianson, 2015; Durden et al., 2018).

Normal bladder function requires coordination of afferent signals originating from the bladder wall with excitatory and inhibitory signals from the anterior cingulate cortex (ACC), insula, and hypothalamus to provide an overview of the appropriateness to urinate that is ultimately under conscious control by the prefrontal cortex (Figure 1; Griffiths, 2015; Lovick, 2016). Bladder afferents embedded within the detrusor smooth muscle show exquisite sensitivity for mechanical distension but are also found innervating the urothelium (Zagorodnyuk et al., 2006, 2007, 2009; Spencer et al., 2018). This topology provides a secondary level of resolution to the transmission of sensory stimuli, including the detection of bladder infection, urothelial inflammation, or barrier breakdown (Figure 1). Accordingly, bladder sensory afferents express a range of anti- and pro-nociceptive receptors and ion channels (Erickson et al., 2018; Grundy et al., 2018c) that integrate the input from this complex signaling environment and can induce a range of sensations from fullness through to pain (Fowler et al., 2008). These afferents, whose cell bodies are located within the dorsal root ganglia (DRG), project via the pelvic, hypogastric/splanchnic nerves, synapse within the dorsal horn of the lumbosacral (LS, L5-S1) and thoracolumbar (TL, T10-L2) spinal cord (Figure 1; Fowler et al., 2008; de Groat and Yoshimura, 2015) and terminate within the periaqueductal gray (PAG) (Fowler et al., 2008). The PAG acts as an integration center for afferent signals from the spinal cord and higher brain centers (Griffiths, 2015). A conscious “urge” to urinate is perceived when afferent activity increases beyond a pre-set threshold and, if modulating input from the brain permits, the PAG activates the pontine micturition centre (PMC) to induce efficient voiding (Andersson and Arner, 2004; Fowler et al., 2008; Griffiths, 2015; Lovick, 2016).

Clinical studies reveal that patients with OAB and IC/PBS perceive sensations of bladder fullness, urge to void, and pain at lower cystometric volumes than healthy subjects (Van Brummen et al., 2004; Kim et al., 2009; Parsons and Drake, 2011). These observations thereby implicate the sensitisation of bladder afferent pathways to physiological stimuli as a key component in the mechanisms underlying these disorders (Yamaguchi et al., 2007; Yoshimura et al., 2014; de Groat and Yoshimura, 2015). Furthermore, co-morbidity of depression and anxiety is significantly higher in patients with OAB and IC/PBS, while high psychological stress levels is strongly correlated to exacerbated bladder symptoms (Goldstein et al., 2008; Lai et al., 2015; Golabek et al., 2016; Leue et al., 2017; McKernan et al., 2017). As such, increased intensity of the afferent signal or modulation of the emotional affective state can have profound effects on bladder sensation. A key concept therefore, in the development of OAB and IC/PBS, is chronic sensitisation of the neuronal networks regulating bladder sensation, incorporating structural, synaptic, or intrinsic changes of peripheral or central structures that may drive subsequent changes in downstream sensory pathways (Brierley and Linden, 2014; Grundy et al., 2018c).

In this review, for brevity, we summarize both preclinical and clinical research to highlight how alterations in peripheral afferent excitability contribute to the symptoms of OAB and IC/PBS to provide insights into the mechanisms that are hypothesized to mediate these distinct disorders which have many overlapping symptoms. For an excellent review on the potential changes in central processes occurring in OAB see Reynolds et al. (2016).

Toxic waste metabolites excreted in urine are prevented from accessing the bladder interstitium and embedded afferent endings by a tight urothelial barrier (Spencer et al., 2018; Figure 1). The urothelial barrier is maintained by tight junctions between apical urothelial cells, hydrophobic uroplakin plaques, and a considerable glycosaminoglycan (GAG) mucus layer, that block the movement of small molecules and urine (Birder and Andersson, 2013; Hurst et al., 2015). From a clinical point of view, numerous studies have identified that patients with IC/PBS, but not OAB, have a diminished or damaged urothelium (Elbadawi and Light, 1996; Tomaszewski et al., 2001; Lai et al., 2013; Keay et al., 2014; Hurst et al., 2015), as well as reduced expression of the tight junction proteins zona occludens 1 (ZO-1) and E-cadherin (Liu et al., 2012). Increased bladder permeability due to reduced urothelial integrity is thought to underlie the sensitivity of IC/PBS patients (75%) to the potassium sensitivity test (PST) compared to control patients (4%) (Parsons et al., 1998). A number of clinical studies also show that OAB patients respond to the PST, however, this may be due to overlap and misdiagnosis between IC/PBS and OAB (Minaglia et al., 2005; MacDiarmid and Sand, 2007; Chung et al., 2010). Despite these observations, it remains to be determined if bladder permeability is part of the underlying pathology of bladder hypersensitivity in IC/PBS patients or a downstream consequence of localized inflammation that further exacerbates the condition.

Glycosaminoglycan replacement therapy with pentosane polysulfate (PPS) has been shown to improve the symptoms for some, but not all, IC/PBS patients (Nickel et al., 2012; Lai et al., 2013; Oliveira et al., 2014; Hurst et al., 2015). However, PPS also induces broad anti-inflammatory actions, including the inhibition of mast cell histamine release in the bladder (Chiang et al., 2000; Anderson and Perry, 2006; Wu et al., 2011; Sanden et al., 2017). In addition, pre-clinical studies inducing urothelial permeability with protamine sulfate identified a relatively rapid recovery of the urothelial barrier and structure (Lavelle et al., 2002; Greenwood-Van Meerveld et al., 2015), via injury-induced proliferation of basal urothelial and stromal cells (Shin et al., 2011). A more likely scenario therefore is that bladder permeability in IC/PBS patients is secondary to localized inflammation. Continuous access of toxic urine contents combined with inflammatory mediators, such as cytokines, histamine, and proteases, can sensitize peripheral afferent endings and have the potential to trigger long term changes in neuronal function and neuroplasticity within the entire afferent network (Brierley and Linden, 2014; Grundy et al., 2018c).

By definition, the presence of bladder inflammation precludes the clinical diagnosis of OAB. Only a small population of IC/PBS patients exhibit significant inflammation, which is characterized by the presence of Hunner’s ulcers (Leiby et al., 2007). However, it is widely reported that there are increases in the amount of pro-inflammatory mediators within the bladder and urine of both OAB and IC/PBS patients (Kastrup et al., 1983; El-Mansoury et al., 1994; Hauser et al., 2008; Jacobs et al., 2010; Liu et al., 2012; Jhang and Kuo, 2016; Furuta et al., 2018). These pro-inflammatory mediators including histamine, nerve growth factor (NGF), and those released from mast cells, are known to directly sensitize afferent nerve terminals (Davidson et al., 2014). Furthermore, overexpression of pro-inflammatory genes, oedema, tissue granulation and an increase in macrophages, chemokines, cytokines, eosinophils, as well as T and B cell markers have also been identified in IC/PBS patients (Hauser et al., 2008; Abernethy et al., 2017). As the majority of cystitis-induced inflammation is localized to the superficial mucosa, urothelial afferents are ideally placed to detect and respond to these environmental changes.

Inflammation-induced sensitisation of afferents is an essential mechanism for the induction of normal wound healing, however, chronic sensitisation of afferents can occur during prolonged inflammation or following a severe bout of inflammation (Brierley and Linden, 2014; Abraham and Miao, 2015). In support of an inflammatory-mediated pathophysiology in urological disorders, animal models of cystitis have employed a range of chemicals, including acetic acid, acrolein, cyclophosphamide (CYP), zymosan and lipopolysaccharide, that induce both acute and longer lasting bladder hyperactivity (Takezawa et al., 2014; Liu and Dong, 2015; Abdi et al., 2016; Hughes et al., 2016). Whilst there are many limitations to the use of inflammatory animal models in the study of symptom defined disorders such as OAB and IC/PBS (comprehensively discussed by Fry et al., 2010), these animals show an overactive bladder phenotype, with altered cystometry and enhanced visceromotor response during bladder distension, replicating the reduced bladder capacity, plus the allodynia and hyperalgesia to bladder distension observed in humans (Fry et al., 2010; Lai et al., 2011; DeBerry et al., 2014, 2015b). Furthermore, bladder afferents show direct sensitisation to chemical and inflammatory stimuli (de Groat and Yoshimura, 2009), whilst retrogradely traced bladder-innervating DRG neurons from CYP-treated rats or a naturally occurring feline interstitial cystitis model exhibit lower activation thresholds and sensitisation to current injection (Dang et al., 2008; Buffington, 2011). The efficacy of intraluminal therapies to treat OAB and IC/PBS (Cvach and Rosamilia, 2015; Manriquez et al., 2015), that either (1) block bladder afferent firing (such as lidocaine and neosaxitoxin) or (2) cause peripheral nerve desensitization (with agents such as resiniferatoxin; RTX), highlight the important role of peripheral afferents in mediating bladder hypersensitivity to distension (Apostolidis et al., 2005).

The transient receptor potential (TRP) channel TRPV1 is upregulated in the bladders of patients with OAB and IC/PBS (Liu and Kuo, 2007), whilst both TRPV1 and TRPA1 have consistently been implicated in mediating normal and cystitis-induced mechanical sensitivity in rodents by modulating neuronal activation thresholds and enhancing bladder afferent responses to P2X receptor activation (Daly et al., 2007; Wang et al., 2008; DeBerry et al., 2014, 2015b; Yoshiyama et al., 2015; Grundy et al., 2018b). A host of additional receptors and channels associated with nociception have also been identified upon bladder afferents that regulate neuronal sensitivity and neuronal excitability in animal models of cystitis, including voltage gated sodium (Na_V) channels (Erickson et al., 2018; Grundy et al., 2018d), potassium channels (K_V) (Hayashi et al., 2009), P2X receptors (Dang et al., 2008; Chen and Gebhart, 2010), TRPV4 (Merrill et al., 2012) and cannabinoid receptors (Hedlund, 2014; Izzo et al., 2015; Bakali et al., 2016; Hedlund and Gratzke, 2016; Munoz, 2016).

It is possible that a population of patients present without active inflammation or increased bladder permeability but are in fact in remission from a preceding bladder infection or inflammation. Such a scenario could induce a protracted hypersensitive state and correspond to their enhanced sensory symptoms. Indeed, women with a clinical history of recurrent UTI as children are significantly more likely to have a diagnosis of IC/PBS as adults (Peters et al., 2009), and preclinical investigations of neonatal bladder insult in rats suggests this may be due to long term sensitisation of sensory pathways (Randich et al., 2006; DeBerry et al., 2007; Ness and Randich, 2010). Neuroplasticity of peripheral afferent circuitry following the resolution of inflammation or recovery from tissue injury has been well documented in both somatic and visceral pain models through the induction of neurogenic inflammation and neuronal sprouting (de Groat and Yoshimura, 2009; Gregory et al., 2013; Brierley and Linden, 2014). Neonatal bladder inflammation in rats results in hypersensitive responses to inflammatory stimuli as an adult, inducing an overactive bladder phenotype (Randich et al., 2006; DeBerry et al., 2007, 2010), as well as enhanced spontaneous and urinary bladder distension-evoked activity of spinal visceral nociceptive neurons (Ness and Randich, 2010). Alterations in spinal cord circuits responsible for bladder sensation may regulate this phenomenon, as neonatal inflammation induces a downregulation of GABA (Aα-1) receptor microRNA and altered opioid peptide content in the dorsal horn (Sengupta et al., 2013; Shaffer et al., 2013). Furthermore, neonatal zymosan enhances bladder neuropeptide content of CGRP and Substance P compared to sham controls (DeBerry et al., 2010; Shaffer et al., 2011).

Similarly, in pre-clinical models of adult cystitis, bladder overactivity is associated with increases in tyrosine receptor kinase (Trk) A, Trk B, and calcitonin gene-related peptide (CGRP) (Vizzard, 2001; Qiao and Vizzard, 2002), which in turn promote inflammation in the tissue where the afferent terminals reside (Rosa and Fantozzi, 2013). Furthermore, patients with IC/PBS have higher elevated serum and urinary NGF levels than healthy controls (Chen et al., 2016). NGF overexpression in mouse urothelium leads to neuronal hyper-innervation, increased mast cell counts and changes in bladder function (Schnegelsberg et al., 2010). These discoveries may explain the increased sprouting of neuronal terminals identified in the bladders of IC/PBS patients (Christmas et al., 1990; Lundeberg et al., 1993), that has been replicated in rodent models of inflammation in vivo and in vitro (Dupont et al., 2001; Schnegelsberg et al., 2010; Boudes et al., 2013; Ekman et al., 2017).

Following the recent identification of a bladder-specific microbiome, and the role of the gut microbiome in chronic functional gastrointestinal diseases (Hughes et al., 2013; Harper et al., 2018), a link between the balance of bacteria in the bladder and the symptoms of OAB and IC/PBS has been postulated and explored (Contreras-Sanz et al., 2016; Angelini, 2017; Drake et al., 2017). Moreover, the traditional colony forming unit thresholds for confirming urinary tract infection (UTI) in clinical practice have been questioned, and a role for chronic UTI in the pathogenesis of OAB has been investigated (Balachandran et al., 2016).

Patients with OAB may have genuine uropathogenic infections, and are therefore misdiagnosed, as large numbers of bacteria are undetected by routine mid-stream urine cultures (Khasriya et al., 2013). Indeed, a significantly greater number of patients with refractory idiopathic detrusor overactivity show low count bacteriuria vs. controls (Walsh et al., 2011). Undiagnosed intracellular bacterial colonization of urothelial cells may also occur in OAB (Scott et al., 2015), as OAB patients exhibit significantly greater infected urothelial cell counts and microscopic pyuria than healthy subjects, which also correlates to urgency symptoms (Gill et al., 2018). Uropathic E. coli infection initiates the release of multiple mediators from the urothelium, including cytokines and interleukins, as well as promoting urothelial barrier defects (Wood et al., 2012), which alert the immune system to impending damage and initiate an immune response (Abraham and Miao, 2015). Immune cell infiltration and the release of pro-inflammatory cytokines are known to sensitize peripheral afferents (Ren and Dubner, 2010), and in this way enhance bladder sensation. In support of these considerations, a recent pilot study revealed that combination antibiotic treatment of both Gram-negative and Gram-positive bacteria significantly improved OAB symptoms as well as the perception of their bladder condition (Vijaya et al., 2013). Furthermore, shifts in the bacterial species that constitute the bladder microbiome have been associated with both the presence and severity of OAB and IC/PBS (Siddiqui et al., 2012; Whiteside et al., 2015; Contreras-Sanz et al., 2016; Lakeman and Roovers, 2016; Curtiss et al., 2017). For example, women with IC/PBS, but not OAB, have a less diverse microbiota than those without (Hilt et al., 2014; Pearce et al., 2014; Abernethy et al., 2017; Curtiss et al., 2017). Interestingly, despite significant inter-patient variability in bladder microbiome, a decrease in Lactobacillus, which has antimicrobial properties, in both OAB and IC/PBS patients compared to controls is a common finding (Hilt et al., 2014; Pearce et al., 2014; Curtiss et al., 2017). Furthermore, the absence of Lactobacillus acidophilus correlates with higher pain scores and higher scores on the interstitial cystitis symptom index (Abernethy et al., 2017). Proteus, the urinary pathogen, is also identified more commonly in patients with OAB and lower urinary tract symptoms than healthy controls (Khasriya et al., 2013; Curtiss et al., 2017). These data support a line of communication between the urinary microenvironment and underlying afferent nerves that is likely mediated by the urothelium.

This review highlights the complex nature of both OAB and IC/PBS, incorporating evidence for changes in the dynamic signaling environment between the bladder lumen, urothelium, and afferent nerves, coordinating with adaptations to the HPA axis, and emotional affective components of sensory processing mediated within the limbic system. The bladder microbiome, bacterial infection, inflammation, and urothelial permeability contribute to the development of peripheral afferent hyperexcitability that is fundamental to the development of frequency and urgency in OAB, and pain in IC/PBS. In addition, the higher psychological stress levels, increased prevalence of anxiety and depression, as well as clinical co-morbidities with other visceral pain disorders suggests pathological plasticity within the CNS is an important component in the mechanisms underlying both OAB and IC/PBS. Determining the underlying mechanisms of bladder hypersensitivity is paramount to providing novel targets for the development of safer and more efficacious treatments.

AC and LG performed literature searches. AC, LG, and SB wrote the manuscript. All authors made significant contributions to the formation and correction of the manuscript in preparation for submission.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.