Cyclophosphamide-induced cystitis in freely-moving conscious rats: Behavioral approach to a new model of visceral pain

Purpose: To develop a model of visceral pain in rats using a behavioral app roach. Cyclophosphamide (CP), an antitumoral agent known to produce toxic e ffects on the bladder wall through its main toxic metabolite acrolein, was used to induce cystitis. Materials and Methods: CP was administered at doses of 50, 100 and 200 mg./ kg. i.p. to male rats, and their behavior observed and scored. The effects of morphine (0.5 to 4 mg./kg. i.v.) on CP-induced behavioral modifications were tested administered alone and after naloxone (1 mg./kg. s.c.). In addi tion, 90 minutes after CP injection, that is, at the time of administration of morphine, the bladder was removed in some rats for histological examina tion. Finally, to show that the bladder is essential for the CP-induced beh avioral modifications, female rats also received CP at doses of 200 mg./kg. i.p. and of 20 mg. by the intravesical route, and acrolein at doses of 0.5 mg. by the intravesical route and of 5 mg./kg. i.v. Results: CP dose-relatedly induced marked behavioral modifications in male rats: breathing rate decrease, closing of the eyes and occurrence of specif ic postures. Morphine dose-dependently reversed these behavioral disorders. A dose of 0.5 mg./kg. produced a reduction of almost 50% of the behavioral score induced by CP 200 mg./kg. This effect was completely prevented by pr etreatment with naloxone. At the time of administration of morphine, histol ogical modifications of the bladder wall, such as chorionic and muscle laye r edema, were observed. In female rats, CP 200 mg./kg. i.p. produced the sa me marked behavioral modifications as those observed in male rats. Administ ered at the dose of 20 mg. intravesically, CP did not produce any behaviora l effects, whereas acrolein at 0.5 mg. intravesically induced behavioral mo difications identical to those under CP 200 mg./kg. i.p., with the same max imal levels. Conversely, acrolein 5 mg./kg. i.v. did not produce any behavi oral effects at all. Conclusions: Overall, these results indicate that this experimental model o f CP-induced cystitis may be an interesting new behavioral model of inflamm atory visceral pain, allowing a better understanding of these painful syndr omes and thus a better therapeutic approach to them.