Intrathecal administration of TRPA1 antagonists attenuate cyclophosphamide-induced cystitis in rats with hyper-reflexia micturition.
BACKGROUND
The activation of TRPA1 channel is implicated in hyper-reflexic micturition similar to overactive bladder. In this study, we aimed to investigate the effects of blocking TRPA1 via intrathecal administration of antagonists on the afferent pathways of micturition in rats with cystitis.


METHODS
The cystitis was induced by intraperitoneal cyclophosphamide administration. Cystometry was performed in control and cystitis rats, following the intrathecal injection of the TRPA1 antagonists HC-030031 and A-967079. Real-time PCR, agarose gel electrophoresis, western blotting and immunohistochemistry were used to investigate the levels of TRPA1 mRNA or protein in the bladder mucosa and L6-S1 dorsal root ganglia (DRG).


RESULTS
Edema, submucosal hemorrhaging, stiffness and adhesion were noted during removal of the inflamed bladder. The expression of TRPA1 mRNA and protein was higher in the cystitis group in both the mucosa and DRG, but the difference was significant in the DRG (P < 0.05). Intrathecal administration of HC-030031 and A-967079 decreased the micturition reflex in the cystitis group. A 50 μg dose of HC-030031 increased the intercontraction interval (ICI) to 183 % of the no-treatment value (P < 0.05) and decreased the non-voiding contraction (N-VC) to 60 % of control (P < 0.01). Similarly, the treatment with 3 μg A-967079 increased the ICI to 142 % of the control value (P < 0.05) and decreased the N-VC to 77 % of control (P < 0.05). The effects of both antagonists weakened approximately 2 h after injection.


CONCLUSIONS
The TRPA1 had a pronounced upregulation in DRG but more slight in mucosa in rat cystitis. The blockade of neuronal activation of TRPA1 by intrathecal administration of antagonists could decrease afferent nerve activities and attenuated detrusor overactivity induced by inflammation.
China Medical University, No. 77 Puhe Road, Shenyang North New Area 110122, Shenyang, Liaoning Province, People's Republic of China.
Zhipeng
Z
Chen
China Medical University, No. 77 Puhe Road, Shenyang North New Area 110122, Shenyang, Liaoning Province, People's Republic of China. dushuqi2015@sina.com.|Department of Urology, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District 110001, Shenyang, Liaoning Province, People's Republic of China. dushuqi2015@sina.com.
Shuqi
S
Du
Department of Urology, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District 110001, Shenyang, Liaoning Province, People's Republic of China.
Chuize
C
Kong
Department of Urology, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District 110001, Shenyang, Liaoning Province, People's Republic of China.
Zhe
Z
Zhang
China Medical University, No. 77 Puhe Road, Shenyang North New Area 110122, Shenyang, Liaoning Province, People's Republic of China.
Al-Dhabi
AD
Mokhtar
D000083:Acetanilides / Q000008:administration & dosage*; D000818:Animals; D003520:Cyclophosphamide / Q000008:administration & dosage; D003556:Cystitis / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D007278:Injections, Spinal; D010091:Oximes / Q000008:administration & dosage*; D011687:Purines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors*; D053201:Urinary Bladder, Overactive / Q000150:complications / Q000503:physiopathology; D014554:Urination
C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; C560402:A 967079; D000083:Acetanilides; D010091:Oximes; D011687:Purines; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D003520:Cyclophosphamide
Antagonist; Cystitis; Rats; TRPA1; Urinary bladder