Mechanisms Underlying Overactive Bladder and Interstitial Cystitis/Painful Bladder Syndrome

Abstract

The bladder is innervated by extrinsic afferents that project into the dorsal horn of the spinal cord, providing sensory input to the micturition centers within the central nervous system. Under normal conditions, the continuous activation of these neurons during bladder distension goes mostly unnoticed. However, for patients with chronic urological disorders such as overactive bladder syndrome (OAB) and interstitial cystitis/painful bladder syndrome (IC/PBS), exaggerated bladder sensation and altered bladder function are common debilitating symptoms. Whilst considered to be separate pathological entities, there is now significant clinical and pre-clinical evidence that both OAB and IC/PBS are related to structural, synaptic, or intrinsic changes in the complex signaling pathways that mediate bladder sensation. This review discusses how urothelial dysfunction, bladder permeability, inflammation, and cross-organ sensitisation between visceral organs can regulate this neuroplasticity. Furthermore, we discuss how the emotional affective component of pain processing, involving dysregulation of the HPA axis and maladaptation to stress, anxiety and depression, can exacerbate aberrant bladder sensation and urological dysfunction. This review reveals the complex nature of urological disorders, highlighting numerous interconnected mechanisms in their pathogenesis. To find appropriate therapeutic treatments for these disorders, it is first essential to understand the mechanisms responsible, incorporating research from every level of the sensory pathway, from bladder to brain.

Therapeutic Efficacy of onabotulinumtoxinA Delivered Using Various Approaches in Sensory Bladder Disorder

“…In OAB patients, urgency is the cardinal symptom along with urinary frequency, nocturia, and urgent incontinence. By contrast, the patients with (IC/PBS) are bothered by bladder pain, urinary frequency, and nocturia [4]. The brief description of probable sensory disturbances occurrence are illustrated in Figure 1.…”

“…OAB has a high prevalence (around 16%-20%) [6], and its symptoms have detrimental effects on individual quality of life and incur societal costs for public health [7]. IC/PBS may develop due to urothelial dysfunction and cause an inflammatory reaction of the bladder and cause permanent inflammatory imprinting in the central nervous system [4]. Dysfunction of the urothelial lining may cause the activation of mast cells and the winding up of capsaicin-sensitive nerves.…”

Effect of Botulinum Toxin A on Bladder Pain—Molecular Evidence and Animal Studies

“…Inflammation-induced afferent sensitization to recruit immune cells is an important protective mechanism to resist infection in the urinary tract [44,45] (Figure 1, part C). However, prolonged inflammation may result in the long-lasting sensitization of afferents and lead to chronic pain [45]. Most experts believe that bladder pain can be attributed to chronic inflammation although the pathogenesis is still inconclusive due to contradictory histopathology results.…”

Tertiary lymphoid tissue develops during normal aging in mice and humans

“…barrier leads to chronic inflammation and disorders such as IC/BPS and rUTIs (7,14,17). Whether 48 urothelial barrier function is affected by aging is not known.…”

“…Here we report distinct, age-5 associated changes to the immune compartment in the otherwise normal female (but not in male) 6 mouse urinary bladder and parallel changes in older women with chronic bladder inflammation. 7 In aged mice, the bladder epithelium became more permeable, and the homeostatic immune 8 landscape shifted from a limited, innate immune-predominant surveillance to an inflammatory, 9 adaptive immune-predominant environment. Strikingly, lymphoid cells were organized into tertiary 10 lymphoid tissues, hereafter named bladder tertiary lymphoid tissue (bTLT).…”