title: Expression and function of CCL2/CCR2 in rat micturition reflexes and somatic sensitivity with urinary bladder inflammation.
abstract: Chemokines are proinflammatory mediators of the immune response, and there is growing evidence for chemokine/receptor signaling involvement in pronociception. Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a chronic pain syndrome characterized by pain, pressure, or discomfort perceived to be bladder-related with at least one urinary symptom. We have explored the expression and functional roles of CCL2 (monocyte chemoattractant protein-1) and its high-affinity receptor, CCR2, in micturition reflex function and somatic sensitivity in rats with urinary bladder inflammation induced by cyclophosphamide (CYP) treatment of varying duration (4 h, 48 h, chronic). Real-time quantitative RT-PCR, ELISAs, and immunohistochemistry demonstrated significant (P ≤ 0.01) increases in CCL2 and CCR2 expression in the urothelium and in Fast Blue-labeled bladder afferent neurons in lumbosacral dorsal root ganglia with CYP-induced cystitis. Intravesical infusion of RS504393 (5 μM), a specific CCR2 antagonist, reduced voiding frequency and increased bladder capacity and void volume in rats with CYP-induced cystitis (4 h), as determined with open outlet, conscious cystometry. In addition, CCR2 blockade, at the level of the urinary bladder, reduced referred somatic sensitivity of the hindpaw and pelvic region in rats with CYP treatment, as determined with von Frey filament testing. We provide evidence of functional roles for CCL2/CCR2 signaling at the level of the urinary bladder in reducing voiding frequency and somatic sensitivity following CYP-induced cystitis (4 h). These studies suggest that chemokines/receptors may be novel targets with therapeutic potential in the context of urinary bladder inflammation.
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT 05405, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Arms
authors.forename: Beatrice M
authors.initials: BM
authors.lastname: Girard
authors.forename: Susan E
authors.initials: SE
authors.lastname: Malley
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Vizzard
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D003520:Cyclophosphamide; D018856:Cystitis, Interstitial / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D007150:Immunohistochemistry; D009475:Neurons, Afferent / Q000378:metabolism; D010147:Pain Measurement; D017288:Pain Threshold; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013141:Spiro Compounds / Q000008:administration & dosage; D013997:Time Factors; D015854:Up-Regulation; D001743:Urinary Bladder / Q000187:drug effects / Q000294:innervation*; D014554:Urination / Q000187:drug effects; D014563:Urodynamics
chemical_list: D048588:Benzoxazines; C491766:Ccl2 protein, rat; C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; D012333:RNA, Messenger; C579117:RS 504393; D054390:Receptors, CCR2; D013141:Spiro Compounds; D003520:Cyclophosphamide
keywords: chemokine/receptor signaling; conscious cystometry; urothelium; von Frey filaments