Involvement of spinal tachykinin NK 1 and NK 2 receptors in detrusor hyperreflexia during chemical cystitis in anaesthetized rats

Abstract

The intraperitoneal administration of cyclophosphamide (150 mg/kg, 48 h before cystometry) induced detrusor hyperreflexia in urethane-anaesthetized rats. Intrathecal administration of the selective tachykinin NK 1 receptor antagonist, GR 82,334 ([ D-Pro 9(spiro-gamma-lactam)Leu 10, Trp 11]physalaemin-(1–11)) (1 nmol/rat i.t.) had no significant effect on micturition in normal rats but increased the volume threshold In cyclophosphamide-treated rats. Another tachykinin NK 1 receptor antagonist, RP 67,580 ((3 aR, 7 aR)-7, 7-diphenyl-2-[1-amino-2(2-methoxyphenyl)ethyl]perhydroisoindol-4-one) (10 nmol/rat i.t.) increased the volume threshold to a similar extent in both vehicle- and cyclophosphamide-treated animals. The tachykinin NK 2 receptor antagonist, SR 48,968 ( S7- N-methyl- N[4-(acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzamide hydrochloride (10 nmol/rat i.t.) did not modify micturition parameters in normal rats but antagonized bladder hyperreflexia in cyclophosphamide-treated animals; SR 48,968 restored the volume threshold for the micturition reflex to values close to control values. SR 48,965 (R7-N-methyl-N[4-(acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzamide hydrochloride) (10 nmol/rat i.t.), the enantiomer of SR 48,968 devoid of affinity for tachykinin NK 2 receptors, was inactive. 2-Amino-5-phosphonovaleric acid (25 and 250 nmol/rat i.t.), a selective antagonist of NMDA receptors, augmented the volume threshold both in controls and in rats with detrusor hyperreflexia; after administration of this antagonist, however, the volume threshold in cyclophosphamide-treated animals was still lower than in controls. Intravenous administration of SR 48,968, RP 67,580, or the combined administration of SR 48,968 and RP 67,580 had no effect on cystometry variables either in rats with detrusor hyperreflexia or in controls. The present results indicate that tachykinin NK 1 and NK 2 receptors located in the spinal cord are involved in bladder hyperreflexia caused by chemically induced cystitis.