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Objective To investigate the role of histamine in spontaneous neuropathic pain following peripheral nerve injury.Methods To prepare the model of spontaneous neuropathic pain (neuroma model), histidine decarboxylase gene knock out (HDC-KO) mice and their wild-type litterrnates (n=14-16/group) underwent complete transection of the sciatic and saphenous nerves unilaterally.Autotomy of mice was scored daily until postoperative day 42.Nav1.3, Nav1.7 and Nay1.8 protein levels in the sciatic nerve and L4/L5 DRGs from both wild-type and HDC-KO mice were measured by immunohistochemistry and west blotting.Results HDC-KO mice showed higher levels of autotomy than wild-types.Nav1.3, Nav1.7 and Nav1.8 protein levels significantly increase in the sciatic nerve after nerve transection both in HDC-KO mice and their wild-type littermates, and presence of endogenous histamine had no effect on this upregulation.Nav1.3 expression was increased, while Nav1.8 was decreased by axotomy in DRGs of both genotypes.However, a role of endogenous histamine was only detected in regulating Nav1.8 expression in DRGs after axotomy.Conclusion These results indicate that endogenous histamine probably suppresses the development of spontaneous neuropathic pain by down-regulating Nav1.8 expression in DRGs.