SEX, TIME-OF-DAY AND ESTROUS VARIATIONS IN BEHAVIORAL AND BLADDER HISTOLOGICAL CONSEQUENCES OF CYCLOPHOSPHAMIDE-INDUCED CYSTITIS IN RATS

This study examined how cyclophosphamide (CP)-induced cystitis related manifestations (bladder inflammation and behavioral impairment) diffe red in female and male Sprague-Dawley rats. Under transient halothane- O-2-N2O gas anesthesia, a single dose of CP was injected (100 mg/kg i. p. in 1 mi saline) and the animal's behaviors analyzed for a period of 4 h using a protocol that permits quantitative analysis of behavioral impairment. The rats were then sacrificed and their bladders removed for histological quantification of inflammation. All CP-injected, but not control rats, exhibited a range of impairment behaviors that incre ased rapidly over a period of 2 h, gradually reaching plateau levels o ver the next 2 h. Female rats initially developed behavioral responses faster than male rats, but reached the same mean peak values overall as males. No sex differences were observed in CP-induced bladder infla mmation. Influences of time-of-day and estrous stage were further exam ined in females. Time-of-day had no effect on the degree of bladder in flammation. Although there were also no significant time-of-day differ ences in behavioral impairments, impairment scores from 90 min after t he injection consistently tended to be lower for rats injected 5 h ver sus 9 h after lights on. Overall, the effects of estrous stage were al so insignificant. However, a subset of rats who were in the estrous st age of their cycle early in the morning of the experimental day develo ped the most severe degree of bladder inflammation, but failed to deve lop the severe behavioral impairments shown by all the other rats. The se results show that there are seemingly only minor sex differences in the overall behavioral and inflammatory consequences of CP injections , as evidenced by similar final degrees of behavioral impairment and i nflammation. These results also suggest, however, that there are sex d ifferences in the etiology of the disease process. These differences a re evidenced by the more rapid development of behavioral symptoms in f emales and the susceptibility of some of those having shown morning es trous smears to develop very severe bladder inflammation in absence of corresponding behavioral impairment. The multiple influences of sex a nd estrous condition on CP-induced cystitis related manifestations obs erved here underline the complexity of the etiological factors associa ted with the cystitis disease process. (C) 1997 International Associat ion for the Study of Pain. Published by Elsevier Science B.V.