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. 2013 Mar 13;29(3):261–269. doi: 10.1007/s12264-013-1316-0

Effects of histamine on spontaneous neuropathic pain induced by peripheral axotomy

Jie Yu 11316, Guo-Dong Lou 11316, Jia-Xing Yue 11316, Ying-Ying Tang 21316, Wei-Wei Hou 11316, Wen-Ting Shou 11316, Hiroshi Ohtsu 31316, Shi-Hong Zhang 11316,✉, Zhong Chen 11316,✉
PMCID: PMC5561842  PMID: 23494529

Abstract

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 loratadine, i.p.) or 21 days (histamine, i.c.v.). Autotomy behavior was scored daily until day 50 post-operation (PO). On days 14 to 21 PO, some rats in the control group were subjected to single-fiber recording. Autotomy behavior was also monitored daily in histidine decarboxylase (the key enzyme for histamine synthesis) knockout (HDC-/-) and wild-type 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 μg/5 μL) significantly suppressed autotomy behavior in rats. HDC-/- mice lacking endogenous histamine showed higher levels of autotomy than the wild-type. In addition, the analgesic effect of histidine was not antagonized by loratadine (a peripherally-acting H1 receptor antagonist), while loratadine alone significantly suppressed autotomy. Electrophysiological recording showed that ectopic spontaneous discharges from the neuroma were blocked by systemic diphenhydramine (an H1 receptor antagonist). Our results suggest that histamine plays an important role in spontaneous NP. It is likely that histamine in the central nervous system is analgesic, while in the periphery, via H1 receptors, it is algesic. This study justifies the avoidance of a histamine-rich diet and the use of peripherally-acting H1 receptor antagonists as well as agents that improve histamine action in the central nervous system in patients with spontaneous NP.

Keywords: histamine, loratadine, H1 receptor, neuropathic pain

Footnotes

These authors contributed equally to this work.

Contributor Information

Shi-Hong Zhang, Email: shzhang713@zju.edu.cn.

Zhong Chen, Email: chenzhong@zju.edu.cn.

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