Morphine treatment for 5 days protects heart against
ischemia-reperfusion (IR) injury. This study evaluated the involvement of
nitric oxide (NO) in
morphine-induced renal protection. Three weeks after right
nephrectomy, increasing doses of
morphine were administered (20-30 mg kg(-1)day(-1), 5 days) to develop dependence in rats. The left kidney underwent 45-min
ischemia and 24-h reperfusion. Some rats were pretreated with
naloxone (5 mg kg(-1)) or
L-NAME (20 mg kg(-1)). In one group, IR was induced 24h after the last dose of
morphine during the withdrawal period. Plasma
nitrite/
nitrate levels and serum
creatinine and BUN were measured.
Creatinine clearance and fractional excretion of
sodium (FE(Na)) were calculated.
Myeloperoxidase (MPO) activity,
malondialdehyde (MDA) level, and inducible
NO synthase (iNOS) expression were determined and histopathology was studied in the left kidney. IR increased serum
creatinine and BUN, plasma NO (p<0.01), FE(Na), iNOS expression (p<0.001), MPO activity, MDA level, and tissue damage and decreased
creatinine clearance.
Morphine decreased plasma NO (p<0.05 vs IR), serum
creatinine and BUN (p<0.01), FE(Na), MPO activity, MDA level, iNOS expression, and tissue damage (p<0.05), but increased
creatinine clearance (p<0.05). Pretreatment with
naloxone significantly increased NO production and iNOS expression in
morphine-treated rats after IR (p<0.01 vs
morphine dependence+IR). Pretreatment with
L-NAME in
morphine-treated rats decreased NO production (10.7+/-1.9, p<0.01 vs
morphine dependence+IR) but could not change iNOS expression after IR. Both
naloxone and
L-NAME significantly abolished the protective effects of
morphine dependence on functional and histological factors. The protective effect of
morphine dependence on serum
creatinine, BUN, FE(Na), and
creatinine clearance persisted during the withdrawal period, whereas iNOS expression decreased. NO production was not decreased during the withdrawal period (p>0.1 vs
morphine dependence+IR group).
Morphine dependence provided renal protection in the acute phase and during withdrawal. Excessive increase or decrease in NO production abolished the effects of
morphine, which suggested a role for balanced NO production and iNOS expression.