CHARACTERIZATION OF THE CAPSAICIN-SENSITIVE COMPONENT OF CYCLOPHOSPHAMIDE-INDUCED INFLAMMATION IN THE RAT URINARY-BLADDER

1 Cyclophosphamide (CYP) (150 mg kg-1, i.p. 0.5-48 h before) caused a time-dependent plasma protein extravasation in the rat urinary bladder with the maximal extravasation occuring at between 2 and 4 h after administration of the drug. 2 Prior capsaicin desensitization of capsaicin-sensitive primary afferent neurones (CSPANs) (50 mg kg-1, s.c., 4 days before) resulted in approximately 50% inhibition of the magnitude of the extravasation response at the 2 h time-point. 3 Intraperitoneal (i.p.) pretreatment with the tachykinin NK, receptor antagomst, RP 67,580 (0.44 mg kg-1) or the bradykinin B2 receptor antagonist, Hoe 140 (0.13 mg kg-1) had significant inhibitory effects, giving responses of 56 +/- 6% and 39 +/- 4% of the control extravasation response to CYP treatment after 2 h. Pretreatment with the tachykinin NK2 receptor antagonist, SR 48,968 (0.3 mg kg-1, i.p.), the histamine H, receptor blocker, chlorpheniramine (10 mg kg-1, i.p.), the 5-HT receptor blocker, methysergide (6mg kg-1, i.p.) or the cyclo-oxygenase inhibitor indomethacin (5 mg kg-1, i.p.) had no significant effect upon the development of the extravasation response at this same time-point. 4 In rat isolated urinary bladder strips, the active metabolite of CYP, acrolein (1 - 300 muM) produced a concentration-dependent contraction that was significantly reduced by in vitro capsaicin desensitization (10 muM for 15 min) indicating direct stimulation of CSPANs. CYP was without appreciable effect. 5 The effect of acrolein in vitro was significantly reduced by pretreatment of the bladder with a combination of tachykinin NK1 and NK2 receptor antagonists, RP 67,580 (3 muM) and SR 48,968 (1 muM). The dose-response curve to acrolein was also significantly inhibited by treatment with indomethacin (10 muM) and slightly affected by Hoe 140 (1 muM). 6 These findings demonstrate the contribution of CSPANs to the development of CYP-induced cystitis. Plasma protein extravasation involves activation of tachykinin NK1 and bradykinin B2 receptors. Activation of CSPANs in the urinary bladder is likely to be due to the conversion of CYP into its active metabolite, acrolein, and not to a direct effect of CYP upon these nerve-endings.