title: Effects of histamine on spontaneous neuropathic pain induced by peripheral axotomy.
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.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Lou
authors.forename: Jia-Xing
authors.initials: JX
authors.lastname: Yue
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Tang
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Hou
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Shou
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohtsu
authors.forename: Shi-Hong
authors.initials: SH
authors.lastname: Zhang
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D019771:Axotomy; D001522:Behavior, Animal / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy*; D009463:Neuroma / Q000188:drug therapy; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000700:Analgesics; D006632:Histamine