Objective To investigate whether the peri pheral administration of amitri ptyl ine and bupivacaine produces anti-hyperalgesic effect and to screen the neurotoxicological effect on sciatic nerve blockade in a rat model of neuropathic pain. Methods Twenty-four adult male SD rats [weighing (200 ± 20) g] were made the models of chronic constriction injury (CCI) and randomly divided into 3 groups (n=8) 5 days after operation: group A (amitriptyl ine), group B (bupivacaine) and group C (normal sal ine). 0.5 mL 0.5% amitriptyl ine, 0.5% bupivacaine or normal sal ine were given in group A, group B, and group C, respectively through implanted cannulas after 5, 7 and 9 days of CCI once a day for successive 3 days. The motor function was measured before administration and 1, 2, 4, 8, 12 and 24 hours after every administration. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured before administration and 1, 3, 5 and 7 days after the third administration. The operated sciatic nerve samples were obtained for neuropathological examination under l ight microscope. Results Twenty-four CCI rats were all survival without infection, palsy and catheter fall ing off. Compared with group C, the rats of group A and group B both produced significant ambulation deficits after every administration (P lt; 0.05). The ambulation deficits lasted 2 hours (group B) and 8 hours (group A) respectively. But the ambulation deficits of CCI rats were all reversible. The MWT and TWL of group A 1 and 3 days after the third administration increased when compared with those before administration and 5 and 7 days after the third administration, and when compared with group B and group C (P lt; 0.05). There was no significant difference (P gt; 0.05) in l ight microscopic neuropathological examination among three groups. Epineurial tissue and endoneurium tissue integrity, tidy arrangement of fibers, less inflammatory cell and no marked degeneration of myel inated fibers were observed. Conclusion Repeated sciatic nerve blockade with 0.5% amitriptyl ine has peripheral anti-hyperalgesic effects on neuropathic pain of rats. No morphological evidence of neurotoxicity in the sciatic nerve of rats is observed in 0.5% amitriptyl ine.