Tolerance to morphine effects on renal disposition of xenobiotics in mice.

Morphine administration (20 mg/kg s.c.) slowed renal elimination of phenol red in mice, raising plasma levels of this dye and reducing its levels in urine. After 9 days of twice daily morphine injections up to 100 mg/kg, an acute 20 mg/kg morphine challenge did not produce analgesia or hypothermia as in naive mice. This multiple dose morphine regimen also induced tolerance to the effects of the narcotic on plasma and urine levels of phenol red. Morphine, 20 mg/kg, reduced plasma p-aminohippurate clearance by 72% in naive mice but only by 56% in tolerant mice. However, reduction of iothalamate clearance after an acute morphine challenge did not show a statistically significant difference between naive and tolerant mice. These findings suggest that tolerance is more readily induced to the effects of narcotic on renal blood flow and/or tubular function than to reduction of glomerular filtration. Tolerance to the acute effects of morphine on phenol red disposition is probably due to lessened response of blood flow or tubular function in chronically dosed mice.