Modulatory role of green tea extract on antinociceptive effect of morphine in diabetic mice.

Diabetic neuropathic pain is an important microvascular complication, and morphine has been demonstrated to be ineffective in this condition. Therefore the present study was designed to investigate the modulatory effect of green tea extract (GTE) on the decreased antinociceptive effect of morphine in diabetic mice. The tail withdrawal test was performed for measurement of the nociceptive threshold in both streptozotocin (STZ)-injected and control mice. Four weeks after administration of STZ, antinociception of morphine (5 mg/kg, s.c.) alone or in combination with GTE (25, 50, and 100 mg/kg, i.p.) was measured. Experimental diabetes markedly decreased the antinociceptive effect of morphine. The decrement in morphine response was significantly attenuated by GTE administration. When GTE (25 mg/kg) and a nitric oxide (NO) inhibitor, L-N(G)-nitroarginine methyl ester (L-NAME) (10 mg/kg, i.p), were co-administered along with morphine (5 mg/kg, s.c) in diabetic mice, the antinociceptive action of morphine was significantly increased as compared with the GTE + morphine-treated diabetic group, but the increased antinociceptive action was significantly attenuated by administration of an NO precursor, L-arginine (100 mg/kg, i.p), instead of L-NAME. Plasma nitrite concentrations were estimated using the Griess reagent. Diabetes significantly increased the plasma nitrite levels that were attenuated by GTE administration. When GTE (25 mg/kg) and L-NAME (10 mg/kg, i.p) were co-administered along with morphine (5 mg/kg, s.c) in diabetic mice, the plasma nitrite levels were significantly decreased as compared with the GTE + morphine alone-treated diabetic group, but the decreased plasma nitrite levels were significantly reversed by administration of L-arginine (100 mg/kg) instead of L-NAME. It may be concluded that increased NO formation may be responsible for the decreased antinociceptive effect of morphine in diabetic mice and that GTE restored the antinociceptive effect of morphine by inhibition of NO production. The results of the present study indicate the possibility of adding GTE as an adjuvant in the treatment of diabetic neuropathic pain.