Effects of glyceryl nonivamide (GLNVA), a nonpungent analogue of capsaicin, on spinal substance P release, blood pressure and renal function were investigated in rats. GLNVA was administered intrathecally or intracerebroventricularly, and renal clearance function was measured. The addition of GLNVA at concentrations of 2, 20 and 200 mumol/l during in vivo spinal superfusion resulted in concentration-dependent increases in the release of substance P. Capsaicin pretreatment (50 mg/kg/day, s.c. for 2 weeks) blunted the GLNVA-induced substance P release, suggesting a stimulation of GLNVA on the spinal terminals of capsaicin-sensitive primary afferent nerves to release substance P. Intracerebroventricular administration of GLNVA at concentrations of 20, 40 and 80 nmol/l evoked a concentration-dependent depressor response. Despite the hypotensive effect, GLNVA caused significant increases in glomerular filtration rate, urine flow, absolute and fractional excretion of sodium and potassium, osmolar clearance and free water reabsorption rate. These data suggest that central administration of GLNVA stimulates spinal substance P release, reduces blood pressure but enhances renal excretion of water and electrolytes due to an increased filtered load and a decreased tubular reabsorption.