Cyclophosphamide-Induced Cystitis in Freely-Moving Conscious Rats: Behavioral Approach to a New Model of Visceral Pain

Boucher, Michel; Méen, Murielle; Codron, Jean-Paul; Coudore, Francois; Kémény, Jean-Louis; Eschalier, Alain

doi:10.1016/s0022-5347(05)67495-2

Cited by 95 publications

(63 citation statements)

References 23 publications

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“…In a previous behavioral study, ip injection of CYP mainly induced a decrease in breathing rate, closing of the eyes and specific immobile postures characterized by rounded back, indicative of CYP-induced nociceptive responses 4. From our preliminary observations (n=6), immobility with a decrease in breathing frequency was considered as a sufficiently reliable parameter.…”

Section: Methodsmentioning

confidence: 71%

“…In animals, intraperitoneal (ip) administration of CYP induces plasma extravasation in the bladder, but not in other abdominal organs 2, and also induces pain behaviors such as decrease in breathing rate, closing of the eyes and specific immobile postures characterized by a rounded back 3,4. Thus, CYP-treated rats have been used as a bladder pain model.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of voiding function and nociceptive behavior in two rat models of cystitis induced by cyclophosphamide or acetone

Saitoh

Yokoyama

Chancellor

et al. 2009

Neurourology and Urodynamics

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Aims-Nociceptive behavior and its relationship with bladder dysfunction were investigated in two cystitis models, which were induced by intraperitoneal (ip) injection of cyclophosphamide (CYP) or intravesical instillation of acetone, using freely moving, non-catheterized conscious rats. Methods-FemaleSprague-Dawley rats were used. Cystitis was induced by ip injection of CYP (100 and 200mg/kg) or intravesical instillation of acetone (10, 30 and 50%) via a polyethylene catheter temporarily inserted into the bladder through the urethra. Then the incidence of nociceptive behavior (immobility with decreased breathing rates) was scored. Voided urine was collected simultaneously and continuously to measure bladder capacity. The plasma extravasation in the bladder was quantified by an evans blue (EB) dye leakage technique.Results-CYP (100mg/kg, ip) induced nociceptive behavior without affecting bladder capacity or EB concentration in the bladder. A higher dose of CYP (200mg/kg, ip) decreased bladder capacity and increased EB levels as well as nociceptive behavior. In contrast, intravesical instillation of acetone (30%) decreased bladder capacity and increased EB levels, but evoked nociceptive behavior less frequently compared with CYP-treated animals. In capsaicin pretreated rats, nociceptive behavior induced by CYP or acetone was reduced; however, the overall effects of CYP or acetone on bladder capacity and bladder EB levels were unaffected.Conclusions-These results suggest that there is a difference in the induction process of nociceptive behavior and small bladder capacity after two different types of bladder irritation and that C-fiber sensitization is more directly involved in pain sensation than reduced bladder capacity.

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Section: Methodsmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Comparison of voiding function and nociceptive behavior in two rat models of cystitis induced by cyclophosphamide or acetone

Saitoh

Yokoyama

Chancellor

et al. 2009

Neurourology and Urodynamics

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“…In addition to hemorrhagic cystitis, systemic CYP treatment causes functional and histological changes similar to BPS/IC including mucosal edema, uroepithelial dysfunction, inflammatory cell infiltration, afferent nerve hyperexcitability, and the development of LUT symptoms [45, 64–67]. CYP administration also produces behavioral alterations consistent with the development of viscerosomatic pain including decreased breathing rate, closing of the eyes, and rounded back postures [66]. While the urinary bladder inflammatory response following systemic CYP administration is greater than what is observed in BPS/IC, this experimental model of cystitis is appealing because of its route of administration (intraperitoneal) and the chronicity and reproducibility of histopathological and functional alterations [47].…”

Section: Bladder Pain Syndrome (Bps)/interstitial Cystitis (Ic)mentioning

confidence: 99%

The Role(s) of Cytokines/Chemokines in Urinary Bladder Inflammation and Dysfunction

Gonzalez

Arms

Vizzard

2014

BioMed Research International

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Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a chronic pain syndrome characterized by pain, pressure, or discomfort perceived to be bladder related and with at least one urinary symptom. It was recently concluded that 3.3–7.9 million women (>18 years old) in the United States exhibit BPS/IC symptoms. The impact of BPS/IC on quality of life is enormous and the economic burden is significant. Although the etiology and pathogenesis of BPS/IC are unknown, numerous theories including infection, inflammation, autoimmune disorder, toxic urinary agents, urothelial dysfunction, and neurogenic causes have been proposed. Altered visceral sensations from the urinary bladder (i.e., pain at low or moderate bladder filling) that accompany BPS/IC may be mediated by many factors including changes in the properties of peripheral bladder afferent pathways such that bladder afferent neurons respond in an exaggerated manner to normally innocuous stimuli (allodynia). The goals for this review are to describe chemokine/receptor (CXCL12/CXCR4; CCL2/CCR2) signaling and cytokine/receptor (transforming growth factor (TGF-β)/TGF-β type 1 receptor) signaling that may be valuable LUT targets for pharmacologic therapy to improve urinary bladder function and reduce somatic sensitivity associated with urinary bladder inflammation.

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“…Earlier studies used intraperitoneal injection of cyclophosphamide, an antitumoral agent, to produce bladder inflammation (Boucher et al 2000) and visceral pain. Although the drug produces selective cystitis via its metabolite, acrolein, in the bladder, it has a severe toxic effect in other organs that can complicate the evaluation of bladder pain.…”

Section: Behavioral Studies For Visceral Pain In Laboratory Animalsmentioning

confidence: 99%

Visceral Pain: The Neurophysiological Mechanism

Sengupta

2009

Handbook of Experimental Pharmacology

164

115

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The mechanism of visceral pain is still less understood compared with that of somatic pain. This is primarily due to the diverse nature of visceral pain compounded by multiple factors such as sexual dimorphism, psychological stress, genetic trait, and the nature of predisposed disease. Due to multiple contributing factors there is an enormous challenge to develop animal models that ideally mimic the exact disease condition. In spite of that, it is well recognized that visceral hypersensitivity can occur due to (1) sensitization of primary sensory afferents innervating the viscera, (2) hyperexcitability of spinal ascending neurons (central sensitization) receiving synaptic input from the viscera, and (3) dysregulation of descending pathways that modulate spinal nociceptive transmission. Depending on the type of stimulus condition, different neural pathways are involved in chronic pain. In early-life psychological stress such as maternal separation, chronic pain occurs later in life due to dysregulation of the hypothalamic–pituitary–adrenal axis and significant increase in corticotrophin releasing factor (CRF) secretion. In contrast, in early-life inflammatory conditions such as colitis and cystitis, there is dysregulation of the descending opioidergic system that results excessive pain perception (i.e., visceral hyperalgesia). Functional bowel disorders and chronic pelvic pain represent unexplained pain that is not associated with identifiable organic diseases. Often pain overlaps between two organs and approximately 35% of patients with chronic pelvic pain showed significant improvement when treated for functional bowel disorders. Animal studies have documented that two main components such as (1) dichotomy of primary afferent fibers innervating two pelvic organs and (2) common convergence of two afferent fibers onto a spinal dorsal horn are contributing factors for organ-to-organ pain overlap. With reports emerging about the varieties of peptide molecules involved in the pathological conditions of visceral pain, it is expected that better therapy will be achieved relatively soon to manage chronic visceral pain.

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Cyclophosphamide-Induced Cystitis in Freely-Moving Conscious Rats: Behavioral Approach to a New Model of Visceral Pain

Abstract: Overall, these results indicate that this experimental model of CP-induced cystitis may be an interesting new behavioral model of inflammatory visceral pain, allowing a better understanding of these painful syndromes and thus a better therapeutic approach to them.

Cited by 95 publications

References 23 publications

Comparison of voiding function and nociceptive behavior in two rat models of cystitis induced by cyclophosphamide or acetone

Comparison of voiding function and nociceptive behavior in two rat models of cystitis induced by cyclophosphamide or acetone

The Role(s) of Cytokines/Chemokines in Urinary Bladder Inflammation and Dysfunction

Visceral Pain: The Neurophysiological Mechanism

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