Neurourology and Urodynamics - 2021 - Sultana - Rodent Models of Ketamine Induced Cystitis

Received: 30 April 2021 | Revised: 25 June 2021 | Accepted: 19 July 2021
DOI: 10.1002/nau.24763
REVIEW
Rodent models of ketamine‐induced cystitis
Saki Sultana1 | Geraint Berger1 | Ashley Cox2 | Melanie E. M. Kelly1,3,4 |

Christian Lehmann1,4,5,6
1
Department of Pharmacology, Dalhousie
University, Halifax, Nova Scotia, Canada Abstract
2
Department of Urology, Dalhousie Aims: Long‐term or recreational use of ketamine affects the urinary system
University, Halifax, Nova Scotia, Canada and can result in ketamine‐induced cystitis (KIC). Rodent models of KIC are
3
Department of Ophthalmology & Visual
important to study KIC pathophysiology and are paramount to the future
Sciences, Dalhousie University, Halifax,
Nova Scotia, Canada development of therapies for this painful condition. This review aims to pro-
4
Department of Anesthesia, Pain vide a summary of rodent models of KIC, focusing on disease induction, ex-
Management & Perioperative Medicine, perimental methods, and pathological features of the model.
Dalhousie University, Halifax,
Nova Scotia, Canada
Method: A literature search was performed using the National Center for
5
Department of Microbiology and Biotechnology Information (NCBI) Pubmed database up to March 2021. 20
Immunology, Dalhousie University, articles met the inclusion criteria and were finally selected.
Halifax, Nova Scotia, Canada
Results: There are considerable variations in the rodent models used for
6
Department of Physiology and
studying KIC in terms of the strain of the animal being used; dose, duration,
Biophysics, Dalhousie University,
Halifax, Nova Scotia, Canada and route of ketamine administration to induce KIC, and assessment of pa-
thological features.
Correspondence
Saki Sultana, Department of
Conclusion: KIC remains difficult to fully recapitulate in humans. Improved
Pharmacology, Dalhousie University, characterization of KIC models and the experimental parameters and meti-
Sir Charles Tupper Medical Bldg, 5850 culous discussion on translational limitations are required to improve the
College St, Room 15AB, Halifax,
NS B3H 4R2, Canada. translational value of research using rodent models of KIC.
Email: saki.sultana@dal.ca
KEYWORDS
cystitis, cystometry, ketamine, rodents, urodynamics
Abbreviations: 2D‐DIGE, 2‐dimensional difference gel electrophoresis; ATP, adenosine triphosphate; CARD10, caspase recruitment domain family
member 10; CD, cluster of differentiation; CD44, a cell surface adhesion receptor; ChIP, chromatin immunoprecipitation; CMG, cystometrogram;
COL1A2, collagen type 1 α2 chain; COL3A1, collagen type 3 α1 chain; COX‐2, cyclooxygenase‐2; CXCL10, C‐X‐C motif chemokine ligand 10;
ELISA, enzyme‐linked immunosorbent assay; eNOS, endothelial nitric oxide synthase; fMRI, functional magnetic resonance imaging; HA, hyaluron;
HAS, hyaluron synthase; H&E, hematoxylin and eosin; ICAM‐1, intercellular adhesion molecule 1; ICR, Institute of Cancer Research;
IgE, immunoglobulin E; IL, interleukin; IL‐1β, interleukin‐1β; IL‐6, interleukin‐6; iNOS, inducible nitric oxide synthase; IP, intraperitoneal;
KIC, ketamine‐induced cystitis; LC‐MS, liquid chromatography‐mass spectrometry; LUTS, lower urinary tract symptoms; mAChR, muscarinic
acetylcholine receptor; MALDI‐TOF, matrix‐assisted laser desportion/ionization‐time of flight; MS, mass Spectrometry; NF‐κB, nuclear factor κ‐light‐
chain‐enhancer of activated B cells; NMDA, N‐methyl‐D‐aspartate; NMDAR, N‐methyl D‐aspartic acid receptor; NOS, nitric oxide synthase;
P2X1, purinergic receptor P2X 1; PAG, periaqueductal gray; PAX5, paired box protein 5; PCR, polymerase chain reaction; qPCR, quantitative
polymerase chain reaction; RHAMM, receptor for hyaluronan‐mediated motility; RT‐qPCR, reverse transcription quantitative polymerase chain
reaction; SD, Sprague‐Dawley; SMAD2, mothers against decapentaplegic homolog 2; SNAI/2/, Snail family transcriptional repressor 1/2/3; TEM,
transmission electron microscopy; TGF‐β, transforming growth factor β; TH1/2/17, T helper type 1/2/17; TLR, toll like receptor; TNF‐α, tumour
necrosis factor α; TRPV1, transient receptor potential cation channel subfamily V member 1; TUNEL, terminal deoxynucleotidyl transferase dUTP
nick end labelling; UPKIII, uroplakin 3; VSOP, voided stain on paper; WB, western blot; ZO‐1, zonula occludens‐1; ↓, decreased/lower/
downregulated; ↑, increased/higher/upregulated.
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SULTANA ET AL. | 1705
1 | INTRODUCTION wall, and dilatation of the ureter wall are some of the
well‐documented pathological features of KIC. 10 Cy-
Validated and predictive animal models are crucial for stoscopic examination in KIC patients shows er-
investigating disease pathology, screening for potential ythema and ulcerations of the bladder mucosa.10
therapeutics, and assessing drug delivery systems at Infiltration of eosinophils, lymphocytes, and plasma
preclinical levels.1 For rare orphan diseases such as cells into the mucosal and submucosal layers of the
ketamine‐induced cystitis (KIC), animal models are im- bladder is observed in mild to moderate cases of
perative to the future development of therapeutics, due to KIC, 11 whereas severe inflammatory conditions are
the difficulty in establishing and performing clinical re- associated with infiltration of mast cells in the mu-
search on these uncommon conditions. In this review, cosa and muscle layers of the bladder.12,13 Muscle
we summarize the rodent models used in the study hypertrophy, submucosal fibrosis, and changes in the
of KIC. collagen muscle ratio are other pathological features
Ketamine is a dissociative anesthetic that was first observed in KIC patient bladders.14 A few studies
introduced for human use in 1970.2 Ketamine produces a have detected higher levels of serum immunoglobulin
wide range of physiological effects including sedation, E (IgE), IL‐6, and IFN‐γ, higher counts of TH1, TH2,
catalepsy, bronchodilation, and somatic analgesia.3 and TH17 cells and reduced levels of TGF‐β in KIC
Well‐established uses of ketamine in clinical practices patients.13,15,16
include intravenous (IV) general anesthesia, relaxation of The severity of KIC symptoms has been shown to
bronchospasm, and analgesia.3 Low‐dose ketamine is be correlated to the dose and frequency of ketamine
also used for the management of acute and chronic pain, intake.9,17 The first case of ketamine cystitis was re-
especially for chronic pain.2,4 Chemically, ketamine is a ported in 2007.17,18 According to a study, about 33% of
phenylpiperidine derivative, structurally related to phen- ketamine abusers develop reduced bladder volume
cyclidine (PCP; “angel dust”) with 2(2‐chlorophenyl)‐2‐ and 30% develop lower urinary tract symptoms
(methylamino)‐cyclohexanone (Figure 1).4 Ketamine can (LUTS).7 While approximately 80% of ketamine abu-
be administered through a variety of routes including sers are males, females typically demonstrate a higher
oral, IV, intramuscular, subcutaneous, and inhalational. level of symptom severity.7 The LUTS associated with
The bioavailability of ketamine varies with the route of KIC typically develops after 1 year of ketamine use at a
its administration.5 Ketamine undergoes hepatic meta- frequency of least 3 times a week, and an average daily
bolism, with norketamine and dehydronorketamine dose of 2 g or more.7,9 However, KIC symptoms may
being the major metabolites excreted through the urine.5 appear as early as 1 month following ketamine usage.
Ketamine administration is associated with several short‐ Cessation of ketamine use usually causes symptom
and long‐term side effects. While short‐term adverse ef- improvement, but symptoms may persist for up to 1
fects of ketamine include drowsiness, hallucination, year after abstinence.18 In a few cases, symptoms may
confusion, involuntary muscle movements and stiffness, progress despite abstinence, with the fibrotic changes
and increased cardiac output,6 long‐term use of ketamine to the bladder contributing to the persistent
can contribute to the development of various mental symptomatology.9
disorders such as attention deficits, and depression, and
the development of urological disorders.4 Repeated high‐
dose consumption of ketamine can lead to physical tol-
erance and drug dependence.4
Aside from therapeutic uses, ketamine is also used
as a recreational drug. Recreational use of ketamine
was first reported in 1967, with the popularity in-
creasing through the 1980s and 1990s, especially
among younger adults. 7 Recreational ketamine is of-
ten a constituent of polysubstance abuse, in combi-
nation with alcohol, stimulants, or other recreational
drugs. 8 Ketamine abuse significantly increases the
risk of developing ulcerative cystitis, 4,7 a painful,
chronic bladder syndrome that presents with high
urinary frequency and urgency, urinary incontinence,
chronic pelvic pain, dysuria, and hematuria. 4,9 Im- FIGURE 1 Chemical structure of ketamine (created with
paired bladder contractions, thickening of the bladder ChemDraw)
1706 | SULTANA ET AL.
2 | METHODS 3.2 | Acute models
A literature search was performed using the National We have found only one study where an acute rodent
Center for Biotechnology Information (NCBI) Pubmed model of KIC has been established. In that study, 12–16
database. The following key terms combinations were weeks old mice on a C57BL/6 background were ad-
used in the literature search: “ketamine‐induced cysti- ministered ketamine into the bladder via an intravesical
tis + rodents,” “ketamine cystitis + rodents,” “ketamine‐ catheter. Direct bladder administration of ketamine
cystitis + rats,” “ketamine‐induced cystitis + rats,” caused acute bladder dysfunction, comparable to long‐
“ketamine‐cystitis + mice,” and “ketamine‐induced cy- term IP injection models. This acute model was used to
stitis + mice.” The literature search was performed in study the effects of Bay k8644, a Cav1.2 agonist, in KIC
March 2021. In total, 20 papers studying ketamine‐ by cystometry.22 This short‐time model may similarly be
induced cystitis in rodents were retrieved. The full text of used for the screening of other drug candidates for the
each paper was examined for the content, the model treatment of urodynamic symptoms associated with KIC.
used, and the outcome of the study. Our inclusion cri-
teria were in vivo studies, and the development of cystitis
upon ketamine administration. We limited our review to 3.3 | Anesthetic considerations for
papers focusing on the impact of ketamine administra- urodynamic studies
tion on the urinary bladder. Papers examining the impact
of ketamine on the kidney were not the focus of this One of the most commonly used techniques for ur-
review. In vitro studies were excluded. For papers with odynamic studies in KIC rodent models is cystometry.
both in‐vitro and in vivo components, we limited our Cystometry can be performed both in conscious and
review to the in vivo results. anesthetized animals. If performed in anesthetized ani-
mals, the choice of anesthetic is a critical decision during
cystometry. Commonly used anesthetics like ketamine,
3 | RODENT MODELS OF KIC pentobarbital sodium, and halothanes suppress contrac-
tion and micturition reflexes in rat bladders.23 Urethane
3.1 | Chronic models is the preferred anesthetic for cytometric procedures as it
has very limited influence on the autonomic nervous
Rodent models used for studying KIC are mainly system, thus has a minimal effect on the micturition
chronic models. Rats are more commonly used for reflex in rodents.24 However, a few studies have reported
inducing KIC in rodents. The popularity of rats over some adverse effects of urethane on the bladder and the
mice could be due to the longer lifespans of rats which lower urinary tract of rodents. In one study, urethane
makes rats more ideal for developing long‐term, was reported to increase the bladder capacity and abolish
chronic KIC models. 19 Rats also provide a larger micturition in rats, suggesting a depressant effect of ur-
bladder for cytometric studies and larger sub- ethane on bladder afferent input.25 Another study re-
urothelium and urothelial areas for simpler analysis ported the blockade of bladder hyperactivity in rats by
of bladder structure and function.20 Adult female urethane.26 In the case of mice, urethane was not re-
Sprague‐Dawley rats are the most commonly used ported to interfere with micturition although it delayed
strain for modeling KIC in rats. In the case of mice, cytometric pressure and elevated the level of maximum
female C57BL/6 are more popular for modeling KIC. contraction pressure.26 In the above‐mentioned studies,
ICR mice showed the appearance of pathogenic fea- the strain of animal used, the disease model, the design
tures of KIC relatively early compared to other strains of the study, the induction time, and the dose of urethane
of mice (Table 2). Intraperitoneal (IP) injection is the were different which should be considered while using
most common route of ketamine administration for urethane as an anesthetic for studying urodynamic be-
the induction of KIC in both rats and mice, however haviors in rodent models of KIC.
oral administration for the induction of KIC has also
been performed. 21 Tables 1 and 2 provide a detailed
summary of the different rodent models of KIC. In- 3.4 | Limitations of rodent models
cluded are the strain, age, and sex of the animal, the of KIC
dose, route of administration and duration of keta-
mine treatment, and the pathological features of the There are limitations to the currently used rodent models of
model. KIC. First, a fixed dose of ketamine is administered to the
TABLE 1 Summary of rat KIC models reported in the literature
Strain, age sex, Ketamine dose and administration Pathological features and major findings
SULTANA
and weight pattern Readouts of KIC model References

ET AL.
39
Adult female SD rats 30 mg/kg, daily IP injection for 28 days – Cystometry – ↑ Peak micturition pressure, frequency,
(200–250 g) – Metabolic cage study nonvoiding contraction frequency
– Ketamine metabolite assay in urine and – ↓ Voiding volume
serum – ↑ Bladder weight, urine ketamine and
– Histologic analysis (Masson's trichrome) norketamine concentrations, and protein:
– Real‐time quantitative PCR (qPCR) and WB creatinine ratio
– Immunostaining – Denuded urothelial mucosa, mononuclear
cell infiltration, interstitial fibrosis, and
collagen accumulation in suburothelium
– ↑ Expression of COX‐2, TGF‐β1, fibronectin,
and type I collagen in bladder tissue
homogenate
– ↑ Receptor expression of CD44, TLR‐4 and
RHAMM, and HA synthases (HAS1, HAS3)
in the urothelial lining
– ↓ Expression of claudin‐4, E‐cadherin, ZO‐1
and UPKIII in the urothelium
40
Adult female SD rats 25 mg/kg daily IP injection for 28 days – Resting‐state fMRI on the PAG region – ↑ Intensity of fMRI signals in the PAG region
(200–240 g) – Metabolic cage study on day 28 of KIC rats
– Liquid chromatography‐mass spectrometry – ↑ Bladder weight, micturition frequency, and
– Cystometry urinary ketamine and norketamine
– Histological (H&E, Masson's trichrome) and concentrations
immunohistochemical analysis – ↑ Intercontractile interval and bladder
– WB compliance
– ↑ Substance P staining in the urothelium,
suburothelial hemorrhage, and monocyte
and macrophage infiltration
– ↑ Collagen I, II, and fibronectin deposition in
the detrusor muscle and damaged uroplakin
III membrane on the apical urothelium
– ↑ Expression of TRPV1 receptor, M2 and
mAChRs in bladder mucosa, and ↑ M2 and
M3‐mAChRs expression in the detrusor
– Upregulation of IL‐1β, IL‐6, TNF‐α, NF‐κB,
COX‐2, TGF‐β1, and ICAM‐1 in the detrusor
41
Adult female SD rats 25 mg/kg, daily IP injection for 28 days – Resting‐state fMRI of the PAG region – Hyperintense fMRI signals of the PAG of
|
(200–250 g) – Metabolic cage study KIC rats
(Continues)
1707
1708
TABLE 1 (Continued)
|
– Cystometry – ↑ Bladder weight, micturition frequency, and
– Ketamine metabolite assay in urine intercontractile intervals
– H&E, and immunostaining for substance – ↑ Concentrations of ketamine and
P and ZO‐1 norketmaine in urine
– Upregulation of IL‐1β, IL‐6, TNF‐α, NF‐κB,
and COX‐2 and overexpression of TRPV1,
M2, and M3‐mAChRs receptors in the
detrusor
– ↑ Red blood cell debris in the suburothelium,
↓ levels of ZO‐1, ↓ expression of E‐cadherin,
and ↑ levels of substance P in the urothelium
14
Adult female SD rats 25 mg/kg, daily IP injection for 14 – Cystometry – ↑ Voiding and nonvoiding contractions
(200–250 g) (K‐14D) or 28 (K‐28D) days – Ketamine metabolite assay in serum and (K‐28D), bladder threshold pressure
urine (K‐28D), maximal micturition pressure
– Histological analysis (Masson’ trichrome) and (K‐28D)
collagen/detrusor smooth muscle ratio – ↓ Bladder compliance (K‐14D and K‐28D)
– WB for COX‐2 and NOS expression – ↑ Urine concentrations of ketamine
– Immunofluorescence metabolites (K‐14D and K‐28D)
– Denuded urothelial mucosa and thin
epithelial layer, red blood cell debris under
suburothelium, and ↑ connective tissue
elements (K‐14D)
– Ulcerated mucosa, erythematous patches in
lamina propria, mononuclear cell
infiltration, and interstitial fibrosis (K‐28D)
– ↑ Expression of COX‐2, iNOS, and eNOS
(K‐14D and K‐28D)
46
Adult male SD rats 50 mg/kg, daily IP injection for 1, 4, or 12 – Metabolic cages study – KIC rats had withered hair, listlessness, ↓
(180–200 g) weeks – Quantification of urinary K+, serum IL‐6 and activity, and significantly less body weight
TNF‐⍺ after 12 weeks
– H&E staining – Two‐hour urinary frequency significantly ↑
– Gas chromatography‐MS analysis after 8 weeks, and the bladder/body
coefficient was significantly ↑ after 12 weeks
– ↑ Levels of serum TNF‐⍺ and IL‐6 in
ketamine‐treated rats after 12 weeks
treatment. Urinary K+ was significantly ↓
SULTANA
after 12 weeks
ET AL.
TABLE 1 (Continued)
SULTANA
ET AL.
– Bladder epithelial necrosis, shedding,

microvascular congestion, and bleeding were
observed after 4 weeks, with significant
neutrophil infiltration present after 12 weeks
– D‐Glutamine, D‐glutamate, arachidonic acid,
glycine, serine, threonine, alanine, aspartate,
glutamate, and inositol phosphate
metabolism altered after 1 and 4 weeks of
ketamine injection
– Linolenic acid, β‐alanine, ascorbate, aldrate,
arachidonic acid, alyoxylate, dicarboxylate,
alycine, serine, threonine, alanine, aspartate,
and glutamate metabolic pathways were
altered after 12 weeks
47
Ten‐week‐old female 25 mg/kg twice weekly, alternating IV – Cystometry – Irregular voiding frequencies, ↓ micturition
SD rats and IP injections for 12 weeks – Histological (H&E, toluidine blue, Masson's intervals, ↓ bladder capacity, ↓ micturition
trichrome) and immunohistochemical volume, ↑ basal pressure, and ↑ maximum
analysis contraction pressure in KIC rat bladders
– Reverse transcriptase and real‐time PCR – Marked infiltration of Toluidine Blue stained
mast cells, TUNEL‐stained apoptotic cells,
and significant tissue fibrosis in KIC rat
bladders
– Upregulation of several fibrosis‐associated
genes, including TGF‐β1 and β2, SMAD2
and 3, and SNAI2 after 12 weeks
48
Ten‐week‐old female 25 mg/kg IV daily for 5 days, followed by – Cystometry – Irregular voiding frequencies, ↓
SD rats a 2‐day rest period, for two cycles – Histological (Toluidine blue, Masson's intercontraction intervals, ↓ bladder
trichrome) and immunohistochemical capacity, and ↑ contraction pressures in
analyses KIC rats
– Reverse transcriptase and real‐time PCR – ↑ Mast cell infiltration, tissue apoptosis, and
tissue fibrosis in KIC rat bladders
– ↑ Expression of TNF‐⍺, CXCL10, IL‐4,
CARD10, TGF‐β1 and β3, SMAD2, SNAI1,
2 and 3 in KIC rat bladders
45
Two‐month‐old male – Two‐dimensional difference gel
SD rats (180–200 g) electrophoresis
|
(Continues)
1709
1710
TABLE 1 (Continued)
|
Two groups: low (10 mg/kg, LK) and – Matrix‐assisted laser desorption ionization‐ – Significant ↑ in micturition frequency in LK
high (50 mg/kg, HK) dose Ketamine time of flight MS and HK groups, with 50% of HK rats
administered daily, IP, for 16 weeks – Histopathological and immunohistochemical exhibiting hematuria
analysis – Fourteen upregulated and 16 downregulated
– WB proteins identified in the HK group
– Uroepithelial thickening and inflammatory
cell infiltration in the submucosa
– ↑ Expression of phosphorylated transgelin in
LK and HK groups compared to the control
group
– ↓ Expression of nonphosphorylated
transgelin in LK and HK groups compared to
the control group
42
Specific pathogen‐free 60 mg/kg daily IP for 16 weeks – Micturition behavior using CuSO4·5H2O – Significant ↑ of micturition frequency, but no
female SD rats gridded filter paper pad change in water intake
(180–210 g), age not – Cystometry – Significant ↑ of voiding frequency and
specified – Histological (H&E, Massson's trichrome) and nonvoiding contractions, and peak pressure
immunohistochemical analysis – Significant ↓ of bladder volume and
– Epithelial to mesenchymal transition compliance
immunofluorescence – Bladder tissue had a thinned epithelium,
– TGF‐β1 quantification ↑ collagen deposition, and fibrosis markers
– ELISA – Significant ↓ of E‐Cadherin staining in the
– RT‐qPCR bladders and significant ↑ of vimentin and
fibronectin staining
– Ketamine treated rat bladders showed
colocalization of E‐cadherin + fibroblast‐
specific protein 1 + cells and E‐cadherin+
⍺‐smooth muscle actin (⍺‐SMA)
– ‐ TBF‐β1 expression in the bladder was
significantly ↑ in the ketamine group
43
Adult male Wistar rats Low dose (L‐KET, 5 mg/kg) and high – Histological analysis (H&E) – Edema, vascular congestion, and leukocyte
(180–200 g), age not dose (H‐KET, 50 mg/kg) groups. infiltration in the bladder tissue, in a dose‐
specified ketmaine administered via IP dependent manner
injection daily for 3 months
SULTANA
ET AL.
TABLE 1 (Continued)
SULTANA
ET AL.
21
Eight‐week‐old male Illicit ketamine combination (38% – Histological analysis (H&E) – Moderate bladder inflammation in 66.7% of
SD rats ketamine hydrochloride, 55% – Immunohistochemical analysis for CD3 rats in the 300 mg/kg group after 4 weeks,
caffeine, and 7% magnesium stearate and PAX5 with lymphocytic infiltration in the
and coloring) at 2 doses: 100 mg/kg submucosal layers of the bladder
and 300 mg/kg administered via oral – No infiltration observed in the 100 mg/kg
gavage daily for 4 or 8 weeks group after 4 weeks
– Animals in the 300 mg/kg group showed
positive immunostaining for CD3 and paired
box protein 5 (PAX5)
– Interstitial nephritis developed in all animals
in the 100 mg/kg group after 4 weeks, but
only in 33% of rats the 300 mg/kg group
– Average weight gain was significantly ↓ in
the 100 mg/kg group, but not the 300 mg/kg
group during week 1
– Bladder inflammation was abolished after 8
weeks of ketamine cessation. Nephritis
persisted in 60% of rats in both groups
44
Adult female SD rats 30 mg/kg daily IP for 3 months – WB (COX‐2 and NF‐κB p65) – COX‐2 and NF‐κB p65 (cytoplasmic and
(250 g, age not – ELISA (PGE2) nuclear) expression significantly ↑ in bladder
specified) – Immunofluorescence (COX‐2 and NF‐κB p65) tissue
– Bisulfate methylation‐specific PCR and – Serum PGE2 concentrations was 3.9‐fold
genome sequencing higher in the ketamine group
– RT‐qPCR – Enhanced staining of NF‐dB p95/DAPI cells
– ChIP sequencing costained with COX‐2 in the ketamine group
restricted to the thinner and disrupted
urothelium
– Hypomethylation of the CpG sites in regions
IV and V of the COX‐2 promoter observed in
the ketamine group
– Hhypomethylation of the COX‐2 promoter
ranging from −1995 to −829 bp
– Significant ↑ of the binding of NF‐κB on the
COX‐2 promoter region ranging from −1522
to −1331 bp
– Significant ↑ of histone H3K4m3
|
methylation, and ↓ histone H3K27m3 and
(Continues)
1711
1712
TABLE 1 (Continued)
|
H3K36m3 methylation on the COX‐2
promoter
– Significant ↑ of mRNA expression of tet
methylcytosine dioxygenases
49
Ten‐week‐old female 1, 5, 10, 25, or 50 mg/kg, daily IV – Cystometry – Voiding intervals, bladder capacity, and
SD rats injection for 2 weeks – Histological (H&E, Massons trichrome, pan‐ compliance ↓ in a dose‐dependent manner.
specific cytokeratin, toluidine blue, and The 10, 25, and 50 mg/kg groups had
TUNEL staining) and immunohistochemical significantly ↓ bladder capacity compared
analysis to sham
– RT‐PCR and real‐time PCR – Thickness of fibrosis increased in a dose
dependent manner, with the 10, 25, and
50 mg/kg showing significant increases
– Nonsignificant ↓ in cytokeratin staining and
↑ toluidine blue stained mast cells
– ↑ Number of apoptotic cells in the
submucosa observed in all ketamine groups
– Bcl‐2‐associated X protein and TNF‐⍺
expression was significantly ↑ in all
ketamine groups
Abbreviations: fMRI, functional magnetic resonance imaging; IP, intraperitoneal; IV, intravenous; mAChR, M3‐muscarinic acetylcholine receptor; PAG, periaqueductal gray; SD, Sprague‐Dawley; TRPV1, transient
receptor potential vanilloid 1; WB, western blot.
SULTANA
ET AL.
TABLE 2 Summary of mouse KIC models reported in the literature
Ketamine dose and
SULTANA
administration Pathological features and major

ET AL.
Strain, age, sex, and weight pattern Readouts findings of KIC model Reference
50
Eight‑week‑old female C57BL/6 mice (19.08 ± 1.29 g) 100 mg/kg, daily IP – Micturition behavior using – ↑ Micturition frequency after 8 and
injection for 4, 8 or CuSO4·5H2O gridded filter 12 weeks of ketamine injections
12 weeks paper pad – Abnormal distribution of ZO‐1 after
– Histological (H&E) and 4, 8, and 12 weeks of ketamine
immunohistochemical analysis injections
– Ultrastructural analysis of the – Flattened umbrella cell surface after
bladder using TEM 4, 8 and 12 weeks. Tight junctions
between umbrella cells became
thinned after 4‐weeks. Vascular
endothelial cells exhibited cell body
shrinkage, increased cytoplasmic
density and chromatin condensation
at 8 weeks, and layer denudation at
12 weeks
– Arteriolar dilatation and vascular
congestion observed after 8 weeks.
Lymphocyte and macrophage
infiltration into the submucosal
epithelium occurred after 12 weeks
of ketamine administration
51
ICR mice, sex not reported (20 g) 30 mg/kg, daily IP – Immunohistochemistry for mast – Significant ↑ in tryptase‐positive
injection for 4, 8, or cell tryptase and E‐cadherin mast cells found in the bladder wall
12 weeks expression after 8 and 12 weeks
– Electron microscopy – ↓ Expression of E‐cadherin in the
8‐ and 12‐week KIC groups
– Ulcerations and epithelial shedding
on the bladders of KIC mice
35
Six‐week‐old male and female Balb/c mice 100 mg/kg daily IP for – Gas chromatography‐MS to – ↑ Concertation of norketamine and
20 weeks detect ketamine and metabolites dehydronorketamine in the urine of
in urine male and female KIC mice
– Voiding behavior using voiding – ↓ In voiding interval of male, but not
stain on paper method female mice at 20 weeks
– Bladder histology using H&E – Rate of weight gain significantly
and Masson's trichrome stain slower following 2 weeks of
– Oligonucleotide DNA ketamine administration, with the
|
microarray effect exacerbated in male mice
(Continues)
1713
1714
TABLE 2 (Continued)
|
Ketamine dose and

– RT‑qPCR – Denser blood vessel distribution in
– Gene pathway building the submucosa of KIC mice
– Upregulation of Col1a2 and Col3a1
gene expression after 20 weeks
– Upregulation of numerous growth
factors, cell mobility, extracellular
matrix remodeling, and angiogenesis
genes after 20 weeks
52
Eight‐week‐old female C57BL/6 mice 100 mg/kg ketamine IP – Cystometry – ↓ Intercontraction interval, bladder
daily for 4, 8, or 16 – Detrusor tension recording capacity, micturition volume, and
weeks – Histological (H&E) and bladder compliance after 8 weeks
immunohistochemical analysis – Significantly lower baseline bladder
pressure after 4 weeks, and
significantly higher after 8, and 16
weeks relative to control
– Noncholinergic electrical field
stimulation evoked contractions of
ketamine‐treated detrusor strips
were significantly ↑ than those of
control after 4 weeks, but not after 8
or 16 weeks
– ↑ In ATP evoked detrusor
contractions after 8, but not 16 weeks
– Mononuclear cell infiltration,
collagen deposition, and urothelial
detachment in ketamine‐treated
bladders after 8 weeks
– ↑ P2X1 receptor immunoreactivity in
the detrusor after 8 and 16 weeks
– Weight gain became significantly
slower, and average micturition
frequency was significantly ↑ after 8
weeks
53
Seven‑week‑old male Balb/c mice 30 mg/kg ketamine IP – Histological (H&E) and – No difference in bladder histology at
for 30 or 60 days immunohistochemical analysis the end of the 30‐ and 60‐day
SULTANA
– Microarray analysis treatment period

ET AL.
TABLE 2 (Continued)
SULTANA
Ketamine dose and

ET AL.
– PCR – Significant ↓ in keratin‐14 expression
in the urothelium after 60 days
– Downregulation of numerous
keratin coding genes after 30 and 60
days of ketamine administration.
The top three downregulated
keratins were keratin 6a, 13, and 14,
confirmed by PCR
54
Two‐month‐old IRC mice 30 mg/kg ketamine IP – Histological (H&E, and – Mononuclear white cell infiltration
for 1, 3, or 6 months Bielshowsky silver staining) near the renal glomeruli,
analysis vasculature, distal and collecting
tubules, papilla and ureter at all time
points
– Thinned uroepithelial layer,
mononuclear infiltration in the
submucosa, and significantly fewer
positive silver‐impregnated fibers
observed in the muscle layer at all
time points
– Significant ↓ in choline
acetyltransferase positive neurons in
all KIC groups
55
Two‐week‐old female C57BL/6 J mice 30 mg/kg ketamine – Void spot assay – Nonsignificant ↑ in voiding
daily IP for 12 – Cystometry frequency, and significant ↓ in
weeks – Immunofluorescence voiding size observed in the
– Electron microscopy ketamine group
– Quantification of permeability – CMG showed that ketamine
and transepithelial resistance treatment caused a significant ↓ in
voiding interval and bladder
compliance, indicative of an
overactive bladder. Ketamine caused
a reduction in peak pressure.
– Ketamine did not disrupt urothelial
barrier function. No significant
changes in urothelial transepithelial
|
resistance, water permeability or

1715
(Continues)
animals over several weeks. This condition does not fully
Abbreviation: ATP, adenosine triphosphate; COL1A2, collagen type 1 α2 chain; COL3A1, collagen type 3 α1 chain; IP, intraperitoneal; KIC, ketamine‐induced cystitis; RT‑qPCR, reverse transcription quantitative
Reference
represent the conditions of ketamine abusers suffering from
KIC who consume ketamine for multiple years. There are
22
also considerable dose variations in street ketamine tablets or
powders, which are often adulterated by amphetamine,
urea permeability were detected. The
– ↓ Voiding interval, peak pressure and

pseudoephedrine, or caffeine. These additional substances
urothelial ultrastructure was not
Pathological features and major
disrupted by chronic ketamine may contribute to the complexity of KIC pathophysiol-

ogy.27,28 Second, ketamine abusers often consume different
forms of ketamine through multiple routes, including IV or
– ↑ In voiding frequency
findings of KIC model
intramuscular injection, intranasally in powder form, in-

halation via smoking, or orally as tablets or added to a
administration
beverage.27,28 The most common route of administration for

compliance
recreational ketamine use is insufflation of the powdered

form,29 with insufflation providing approximately 50% bioa-
vailability.30 This route of administration has not been re-
ported in the rodent models of KIC in the literature, based
on our search. Replicating the variability in human ketamine
intake with respect to ketamine purity, frequency of use, and
route of administration remains a challenge in the attempt of
developing a clinically relevant model for KIC.
The effect of long‐term use of ketamine could also be
different in males and females, potentially due to differences
in hormones and metabolic enzymes. Sex is a variable that
– Cystometry
can influence all pharmacokinetic processes, including ab-

sorption, distribution, metabolism, and excretion.31 As re-
Readouts
ported in the literature, female rodents are more commonly

being used for studying KIC pathology. However, various
demographic studies have shown that males are the more
12–16‐week‐old C57BL/6J mice (plus various knockout mice on Intravesical infusion of
common consumers of nonprescribed ketamine,32,33 and

Ketamine dose and
ketamine (100 µg/

ml, 500 µg/ ml)
KIC is more prominent among males.32,34 In the study by

administration
Shen et al., male and female Balb/c mice were used to study
the pathophysiology of KIC. The results showed that long‐
pattern
term ketamine administration had a greater effect on body

weight and voiding behavior in male mice compared to fe-
male counterparts.35 Another study investigating sex and
dose‐dependent abuse liability of ketamine using SD rats
polymerase chain reaction; TEM, transmission electron microscopy.
reported that female rats are more sensitive than male rats to
ketamine's stimulant properties. However, they did not in-
vestigate the effect of ketamine on bladder function.36
Moreover, female rats have shown greater concentrations of
ketamine and norketamine shortly after administration in
both the brain and plasma, as well as slower clearance rats
and longer half‐lives.31 Therefore, the effects of sex difference
on ketamine pharmacokinetics should be considered and
Strain, age, sex, and weight
rationalized when selecting a rodent model of KIC.

a C57BL/6J background)
Another potential limitation of some of the rodent

(Continued)
models used to study KIC is that animals are sometimes

administered ketamine for 16–20 weeks. This is a long
treatment period considering the life span of rodents, espe-
cially mice. Therefore, the effect of aging on the bladder or
TABLE 2
the urodynamic behavior of rodents should be taken into

consideration while performing these long‐term studies.
Studies have shown that aging causes myogenic and
neurogenic changes to the mouse bladder which contribute with Ashley Cox, Melanie E. M. Kelly, and Christian
to voiding and storage dysfunction.37 Other studies have also Lehmann. All authors reviewed and edited the manuscript
shown age‐related impacts on bladder function, with aging and contributed to the final version of the manuscript.
inducing overactivity and hypersensitivity of the mouse
bladder.38 Therefore, rodent age at the start and end of the ORC ID
experimental time course should be carefully considered in Saki Sultana http://orcid.org/0000-0003-1929-0805
conjunction with these results, with age‐matched controls
being an essential component of long‐term studies. REFER ENCES
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https://doi.org/10.1002/nau.24763

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Received: 30 April 2021 | Revised: 25 June 2021 | Accepted: 19 July 2021

Rodent models of ketamine‐induced cystitis

Saki Sultana1 | Geraint Berger1 | Ashley Cox2 | Melanie E. M. Kelly1,3,4 |

2 | METHODS 3.2 | Acute models

and weight pattern Readouts of KIC model References

(200–250 g) – Metabolic cage study KIC rats

– Bladder epithelial necrosis, shedding,

methylation, and ↓ histone H3K27m3 and

administration Pathological features and major

microarray effect exacerbated in male mice

Ketamine dose and

– Microarray analysis treatment period

Ketamine dose and

resistance, water permeability or

animals over several weeks. This condition does not fully

– ↓ Voiding interval, peak pressure and

disrupted by chronic ketamine may contribute to the complexity of KIC pathophysiol-

intramuscular injection, intranasally in powder form, in-

beverage.27,28 The most common route of administration for

recreational ketamine use is insufflation of the powdered

can influence all pharmacokinetic processes, including ab-

ported in the literature, female rodents are more commonly

common consumers of nonprescribed ketamine,32,33 and

ketamine (100 µg/

KIC is more prominent among males.32,34 In the study by

term ketamine administration had a greater effect on body

rationalized when selecting a rodent model of KIC.

Another potential limitation of some of the rodent

models used to study KIC is that animals are sometimes

the urodynamic behavior of rodents should be taken into

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