Objective To investigate the efficiency of intracerebroventricular injection of histamine receptor antagonists on mechanical pain threshold of neuropathic pain in rats. Methods The neuropathic pain rat model was established by partially ligation of the sciatic nerve in 30 rats. Two weeks later, histamine receptor 1 antagonist pyrilamine 1.5 μg or 15 μg was injected intracerebroventricularly in group P1 or P2, histamine receptor 2 antagonist ranitidine 10 μg or 100 μg in group R1 or R2, and normal saline in group C as the control. The pain threshold was measured. Results Compaered with group C,the pain threshold was signifigantly increased in group R1 and R2, especially in group R2 (P<0.05). Conclusion Histamine H2 receptor antagonist can increase pain threshold in rats with neuropathic pain.