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 ad ministration of the drug. 2 Prior capsaicin desensitization of capsaic in-sensitive primary afferent neurones (CSPANs) (50 mg kg-1, s.c., 4 d ays 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 ant agonist, SR 48,968 (0.3 mg kg-1, i.p.), the histamine H, receptor bloc ker, chlorpheniramine (10 mg kg-1, i.p.), the 5-HT receptor blocker, m ethysergide (6mg kg-1, i.p.) or the cyclo-oxygenase inhibitor indometh acin (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 isolat ed urinary bladder strips, the active metabolite of CYP, acrolein (1 - 300 muM) produced a concentration-dependent contraction that was sign ificantly reduced by in vitro capsaicin desensitization (10 muM for 15 min) indicating direct stimulation of CSPANs. CYP was without appreci able effect. 5 The effect of acrolein in vitro was significantly reduc ed 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 t o the development of CYP-induced cystitis. Plasma protein extravasatio n involves activation of tachykinin NK1 and bradykinin B2 receptors. A ctivation 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 d irect effect of CYP upon these nerve-endings.