Antagonism of the transient receptor potential ankyrin 1 (TRPA1) attenuates hyperalgesia and urinary bladder overactivity in cyclophosphamide-induced haemorrhagic cystitis

• Published in: Chemico-biological interactions 2013-04, Vol.203 (2), p.440-447
• Main Authors: Meotti, Flavia C., Forner, Stefânia, Lima-Garcia, Juliana F., Viana, Alice F., Calixto, João B.
• Format: Article
• Language: English
• Subjects: Acetanilides - pharmacology; Acetanilides - therapeutic use; Acrolein; adverse effects; Animals; antagonists; Antineoplastic Agents, Alkylating - adverse effects; bladder; Bladder overactivity; chemotherapy; Cyclophosphamide; Cyclophosphamide - adverse effects; cystitis; Cystitis - chemically induced; Cystitis - complications; Cystitis - metabolism; Cystitis - physiopathology; Female; Hemorrhage - complications; Hyperalgesia - complications; Hyperalgesia - drug therapy; locomotion; Purines - pharmacology; Purines - therapeutic use; Rats; TRPA1; TRPA1 Cation Channel; TRPC Cation Channels - antagonists & inhibitors; Urinary Bladder, Overactive - complications; Urinary Bladder, Overactive - drug therapy; Urodynamics - drug effects; Urotoxicity
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2013.03.008

•Cyclophosphamide caused bladder overactivity in rats.•The urotoxic effects were associated to a nociceptive behavior.•Overactivity and nociception were dependent on TRPA1.•Cyclophosphamide metabolite acrolein might be triggering the urotoxicity. The aim of this study was to investigate the involvement of the transient receptor potential ankyrin 1 (TRPA1) in haemorrhagic cystitis, the main side effect of cyclophosphamide-based chemotherapy. Hannover female rats received intraperitoneal (i.p.) injection of cyclophosphamide (three doses of 100mg/kg, every other day, in a total of five days). This treatment was followed by the treatment with TRPA1 antagonist HC 030031 (50mg/kg, p.o.). The threshold for hindpaw withdrawal or abdominal retraction to von Frey Hair and the locomotor activity were measured. The treatment with the TRPA1 antagonist HC 030031 significantly decreased mechanical hyperalgesia induced by cyclophosphamide without interfere with locomotor activity. Urodynamic parameters were performed by cystometry 24h after a single treatment with cyclophosphamide (200mg/kg, i.p.) in control and HC 030031 treated rats. Analyses of the urodynamic parameters showed that a single dose of cyclophosphamide was enough to significantly increase the number and amplitude of non-voiding contractions and to decrease the voided volume and voiding efficiency, without significantly altering basal, threshold or maximum pressure. The treatment with HC 030031 either before (100mg/kg, p.o.) or after (30mg/kg, i.v.) cyclophosphamide inhibited the non-voiding contractions but failed to counteract the loss in voiding efficiency. Our data demonstrates that nociceptive symptoms and urinary bladder overactivity caused by cyclophosphamide, in part, are dependent upon the activation of TRPA1. In this context, the antagonism of the receptor may be an alternative to minimise the urotoxic symptoms caused by this chemotherapeutic agent.