The role of C‐fibers in the development of chronic psychological stress induced enhanced bladder sensations and nociceptive responses: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study

Gao, Yunliang; Zhang, Rong; Chang, Haṡok; Rodríguez, Larissa V.

doi:10.1002/nau.23374

Cited by 27 publications

(45 citation statements)

References 30 publications

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“…Similarly, in animal models (WAS, chronic social defeat, and social stress), chronic stress results in visceral hypersensitivity and alterations in structure and function of the urinary bladder . These include bladder wall remodeling, mast cell infiltration and angiogenesis, increased voiding frequency, reduced voided volume, and increased visceral hypersensitivity during bladder filling . Our study provides the foundation for a mechanism linking these stressors to bladder abnormalities through changes in the urothelial mitochondria.…”

Section: Discussionmentioning

confidence: 65%

“…[12][13][14] These include bladder wall remodeling, mast cell infiltration and angiogenesis, increased voiding frequency, reduced voided volume, and increased visceral hypersensitivity during bladder filling. [9][10][11][12][13][14] Our study provides the foundation for a mechanism linking these stressors to bladder abnormalities through changes in the urothelial mitochondria. A main finding of our study was a more depolarized Ψm which was associated with a tendency toward increased SRC and maximal respiration.…”

Section: Chronic Stress Effects On Bladder Function and Visceral Sementioning

confidence: 82%

“…8 In rats predisposed to anxiety, chronic stress induced by water avoidance stress (WAS) results in clinical and functional features reminiscent of human IC/BPS. [9][10][11][12][13][14] Treatment with an adrenergic antagonist prevents the emergence of these features. 11 Stress-induced sympathetic dysregulation could therefore trigger this bladder dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Stress‐induced autonomic dysregulation of mitochondrial function in the rat urothelium

Kullmann

McDonnell

Wolf‐Johnston

et al. 2018

Neurourology and Urodynamics

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Aim Chronic stress exacerbates the symptoms of most pain disorders including interstitial cystitis/bladder pain syndrome (IC/BPS). Abnormalities in urothelial cells (UTC) occur in this debilitating bladder condition. The sequence of events that might link stress (presumably through increased sympathetic nervous system‐SNS activity) to urothelial dysfunction are unknown. Since autonomic dysregulation, mitochondrial dysfunction, and oxidative stress all occur in chronic pain, we investigated whether chronic psychological stress initiated a cascade linking these three dysfunctions. Methods Adult female Wistar Kyoto rats were exposed to 10 days of water avoidance stress (WAS). Bladders were then harvested for Western blot and single cell imaging in UTC cultures. Results UTC from WAS rats exhibited depolarized mitochondria membrane potential (Ψm ∼30% more depolarized compared to control), activated AMPK and altered UT mitochondria bioenergetics. Expression of the fusion protein mitofusion‐2 (MFN‐2) was upregulated in the mucosa, suggesting mitochondrial structural changes consistent with altered cellular metabolism. Intracellular calcium levels were elevated in cultured WAS UTC, consistent with impaired cellular function. Stimulation of cultured UTC with alpha‐adrenergic (α‐AR) receptor agonists increased reactive oxidative species (ROS) production, suggesting a direct action of SNS activity on UTC. Treatment of rats with guanethidine to block SNS activity prevented most of WAS‐induced changes. Conclusions Chronic stress results in persistent sympathetically mediated effects that alter UTC mitochondrial function. This may impact the urothelial barrier and signaling, which contributes to bladder dysfunction and pain. This is the first demonstration, to our knowledge, of a potential autonomic mechanism directly linking stress to mitochondrial dysfunction.

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Section: Discussionmentioning

confidence: 65%

Section: Chronic Stress Effects On Bladder Function and Visceral Sementioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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Stress‐induced autonomic dysregulation of mitochondrial function in the rat urothelium

Kullmann

McDonnell

Wolf‐Johnston

et al. 2018

Neurourology and Urodynamics

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“…Chronic WAS is another well‐known model highly relevant to human IC/BPS without Hunner lesions. Rats exposed to WAS showed bladder hypersensitivity symptoms including a decreased threshold of micturition, increased urinary frequency and hyperalgesia 134–136 . The rats also showed increased subepithelial MC infiltration and urinary NGF levels, 137,138 with increased engagement and connectivity of brain micturition neuronal circuits and motor cortex regions 135 .…”

Section: Animal Modelsmentioning

confidence: 99%

Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives

et al. 2020

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Abbreviations & Acronyms BPS = bladder pain syndrome CCL2 = C-C motif ligand 2 CNS = central nervous system DMSO = dimethyl sulfoxide EAC = experimental autoimmune cystitis ESSIC = International Society for the Study of BPS FSS = functional somatic syndrome GAG = glycosaminoglycan IC = interstitial cystitis IFN-c = interferon-gamma IL = interleukin MC = mast cell NGF = nerve growth factor OVA = ovalbumin TCR = T-cell receptor TNF = tumor necrosis factor TLR = Toll-like receptor UCPPS = urological chronic pelvic pain syndrome UPK = uroplakin Upo = unpublished observation VEGF = vascular endothelial growth factor WAS = water avoidance stress Correspondence: Yoshiyuki Abstract: Interstitial cystitis/bladder pain syndrome is a debilitating condition of unknown etiology characterized by persistent pelvic pain with lower urinary tract symptoms and comprises a wide variety of potentially clinically useful phenotypes with different possible etiologies. Current clinicopathological and genomic evidence suggests that interstitial cystitis/bladder pain syndrome should be categorized by the presence or absence of Hunner lesions, rather than by clinical phenotyping based on symptomatology. The Hunner lesion subtype is a distinct inflammatory disease with proven bladder etiology characterized by epithelial denudation and enhanced immune responses frequently accompanied by clonal expansion of infiltrating B cells, with potential engagement of infection. Meanwhile, the non-Hunner lesion subtype is a noninflammatory disorder with little evidence of bladder etiology. It is potentially associated with urothelial malfunction and neurophysiological dysfunction, and frequently presents with somatic and/or psychological symptoms, that commonly result in central nervous sensitization. Animal models of autoimmune cystitis and neurogenic sensitization might serve as disease models for the Hunner lesion and non-Hunner lesion subtypes, respectively. Here, we revisit the taxonomy of interstitial cystitis/bladder pain syndrome according to current research, and discuss its potential pathophysiology and representative animal models. Categorization of interstitial cystitis/bladder pain syndrome based on cystoscopy is mandatory to design optimized treatment and research strategies for each subtype. A tailored approach that specifically targets the characteristic inflammation and epithelial denudation for the Hunner lesion subtype, or the urothelial malfunction, sensitized/altered nervous system and psychosocial problems for the non-Hunner lesion subtype, is essential for better clinical management and research progress in this complex condition.

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“…14,15 Consistent with this, the MAPP research network has recently identified potential central biological markers for IC/BPS, which include functional alterations in a sensorimotor network, abnormal connectivity of posterior medial cortex, and brain microstructural changes associated with chronic pain, bladder function, and symptom severity. [16][17][18][19][20][21][22][23][24] Our prior work [25][26][27][28][29] has employed a reverse translational rodent model that parallels the clinical phenotype of IC/BPS, in particular the role of chronic stress in the development and maintenance of urinary symptoms and bladder hypersensitivity, 2,[30][31][32][33][34] as well as general pain sensitivity in susceptible individuals predisposed to anxiety. 8,[35][36][37][38][39] In this model, we have demonstrated that chronic water avoidance stress (WAS) leads to urinary frequency, bladder hyperalgesia, and increased somatosensory nociceptive reflex responses that persist up to 1 month following removal of the stressor.…”

Section: Introductionmentioning

confidence: 99%

Ceftriaxone inhibits stress‐induced bladder hyperalgesia and alters cerebral micturition and nociceptive circuits in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome research network study

Holschneider¹,

Wang²,

Chang

et al. 2020

Neurourology and Urodynamics

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Aims Emotional stress plays a role in the exacerbation and development of interstitial cystitis/bladder pain syndrome (IC/BPS). Given the significant overlap of brain circuits involved in stress, anxiety, and micturition, and the documented role of glutamate in their regulation, we examined the effects of an increase in glutamate transport on central amplification of stress‐induced bladder hyperalgesia, a core feature of IC/BPS. Methods Wistar‐Kyoto rats were exposed to water avoidance stress (WAS, 1 hour/day x 10 days) or sham stress, with subgroups receiving daily administration of ceftriaxone (CTX), an activator of glutamate transport. Thereafter, cystometrograms were obtained during bladder infusion with visceromotor responses (VMR) recorded simultaneously. Cerebral blood flow (CBF) mapping was performed by intravenous injection of [14C]‐iodoantipyrine during passive bladder distension. Regional CBF was quantified in autoradiographs of brain slices and analyzed in three dimensional reconstructed brains with statistical parametric mapping. Results WAS elicited visceral hypersensitivity during bladder filling as demonstrated by a decreased pressure threshold and VMR threshold triggering the voiding phase. Brain maps revealed stress effects in regions noted to be responsive to bladder filling. CTX diminished visceral hypersensitivity and attenuated many stress‐related cerebral activations within the supraspinal micturition circuit and in overlapping limbic and nociceptive regions, including the posterior midline cortex (posterior cingulate/anterior retrosplenium), somatosensory cortex, and anterior thalamus. Conclusions CTX diminished bladder hyspersensitivity and attenuated regions of the brain that contribute to nociceptive and micturition circuits, show stress effects, and have been reported to demonstrated altered functionality in patients with IC/BPS. Glutamatergic pharmacologic strategies modulating stress‐related bladder dysfunction may be a novel approach to the treatment of IC/BPS.

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The role of C‐fibers in the development of chronic psychological stress induced enhanced bladder sensations and nociceptive responses: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study

Cited by 27 publications

References 30 publications

Stress‐induced autonomic dysregulation of mitochondrial function in the rat urothelium

Stress‐induced autonomic dysregulation of mitochondrial function in the rat urothelium

Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives

Ceftriaxone inhibits stress‐induced bladder hyperalgesia and alters cerebral micturition and nociceptive circuits in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome research network study

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