The present study was designed to investigate the effects of histamine on spontaneous neuropathic pain （NP） induced by peripheral axotomy. Rats and mice were subjected to complete transection of the left sciatic and saphenous nerves to induce spontaneous NP （the neuroma model）. Rats were then treated with drugs once daily for 30 days （histidine and Ioratadine, i.p.） or 21 days （histamine, i.c.v.）. Autotomy behavior was scored daily until day 50 postoperation （PO）. On days 14 to 21 PO, some rats in the control group were subjected to singlefiber recording. Autotomy behavior was also monitored daily in histidine decarboxylase （the key enzyme for histamine synthesis） knockout （HDC/） and wildtype mice for 42 days. We found that both histidine （500 mg/kg） （a precursor of histamine that increases histamine levels in the tissues） and histamine （50 pg/5 pL） significantly suppressed autotomy behavior in rats. HDC mice lacking endogenous histamine showed higher levels of autotomy than the wildtype. In addition, the analgesic effect of histidine was not antagonized by Ioratadine （a peripherallyacting H1 receptor antago nist）, while Ioratadine alone significantly suppressed autotomy. Electrophysiological recording showed that ectopic spontaneous discharges from the neuromawere blocked by systemic diphenhydramine （an H receptor antagonist）. Our results suggest that hista mine plays an important role in spontaneous NP. It is likely that histamine in the central nervous system is analgesic, while in the periphery, via H receptors, it is algesic. This study justifies the avoidance of a histaminerich diet and the use of peripherallyacting H receptor antagonists as well as agents that improve histamine action in the central nervous system in pa tients with spontaneous NP.
Jie YuGuo-Dong LouJia-Xing YueYing-Ying TangWei-Wei HouWen-Ting ShouHiroshi OhtsuShi-Hong ZhangZhong Chen
