Effects of multiple intrathecal administration of L-arginine with different doses on formalin-induced nociceptive behavioral responses in rats

Objective To investigate the effects of nitric oxide (NO) with different doses on modulation of inflammatory pain, and its possible mechanisms. Methods NO precursor L-arginine (L-Arg) was intrathecally administered in rats at a dose of 10 mu g per day (low dose group) or 250 mu g per day (high dose group) for a succession of 4 d. Normal saline was applied as a control. Then the rats were subcutaneously injected with formalin (100 mu L, 2%) into the right hindpaw, and the nociceptive behavioral responses within 1 h were observed. At 4 h after formalin injection, neuronal NO synthase (nNOS) and c-Fos expression in spinal dorsal horn was examined with immunocytochemistry method. Results The subcutaneous injection of formalin evoked biphasic behaviors of licking or biting the injected paw. There was no difference in acute phase of formalin test among the 3 groups, while in tonic phase, the licking and biting time, and the protein levels of nNOS and c-Fos in spinal dorsal horn were significantly decreased in low dose group and increased in high dose group, compared with those in control group. Conclusion These results suggest that multiple administration of NO with different doses may produce different effects. On one hand, the low dose of NO can induce antinociception. On the other hand, the high dose of NO can induce pronociception.