Urinary bladder
pain is a primary symptom associated with
interstitial cystitis/
painful bladder syndrome. We used systemic
injections of
cyclophosphamide (CYP), an alkylating
antineoplastic agent, to induce
cystitis and examine the roles of 2 channels previously demonstrated to be required for inflammatory visceral
hyperalgesia: transient receptor potential vanilloid-1 (TRPV1) and ankyrin-1 (TRPA1). Injection of CYP (100 mg/kg, i.p.) every other day for 5 days was accompanied by bladder
edema and urothelial ulceration, but without significant plasma extravasation or infiltration of neutrophils.
Toluidine blue staining showed a significant increase in the number of degranulated bladder mast cells after CYP treatment. Despite this mild pathology, CYP-treated mice exhibited bladder
hyperalgesia 1 day after the final injection that persisted 7 days later. Although many previous studies of visceral
hyperalgesia have reported changes in dorsal root ganglion neuron TRPV1 expression and/or function, we found no change in bladder afferent TRPV1 expression or sensitivity on the basis of the percentage of bladder afferents responsive to
capsaicin, including at submaximal concentrations. In contrast, the percentage of bladder afferents expressing functional TRPA1
protein (i.e., those responsive to mustard oil) increased ∼2.5-fold 1 day after CYP treatment, and remained significantly elevated 7 days later. Moreover, bladder
hyperalgesia was reversed by acute treatment with the TRPA1 antagonist
HC-030031 (300 mg/kg, i.p.). Our results indicate that CYP-induced bladder
hyperalgesia can be induced without robust
inflammation or changes in primary afferent TRPV1. However, significant changes were observed in TRPA1 expression, and blockade of TRPA1 alleviated CYP-induced bladder
hyperalgesia.