title: A critical time window for the analgesic effect of central histamine in the partial sciatic ligation model of neuropathic pain.
abstract: It is known that histamine participates in pain modulation. However, the effect of central histamine on neuropathic pain is not fully understood. Here, we report a critical time window for the analgesic effect of central histamine in the partial sciatic nerve ligation model of neuropathic pain.
  
  
  
  Neuropathic pain was induced by partial sciatic nerve ligation (PSL) in rats, wild-type (C57BL/6J) mice and HDC(-/-) (histidine decarboxylase gene knockout) and IL-1R(-/-) (interleukin-1 receptor gene knockout) mice. Histidine, a precursor of histamine that can increase the central histamine levels, was administered intraperitoneally (i.p.). Histidine decarboxylase (HDC) enzyme inhibitor α-fluoromethylhistidine was administered intracerebroventricularly (i.c.v.). Histamine H1 receptor antagonist mepyramine and H2 receptor antagonist cimetidine were given intrathecally (i.t.) and intracisternally (i.c.). Withdrawal thresholds to tactile and heat stimuli were measured with a set of von Frey hairs and infrared laser, respectively. Immunohistochemistry and Western blot were carried out to evaluate the morphology of microglia and IL-1β production, respectively.
  
  
  
  Histidine (100 mg/kg, i.p.) administered throughout days 0-3, 0-7, or 0-14 postoperatively (PO) alleviated mechanical allodynia and thermal hyperalgesia in the hindpaw following PSL in rats. Intrathecal histamine reversed PSL-induced thermal hyperalgesia in a dose-dependent manner and intracisternal histamine alleviated both mechanical allodynia and thermal hyperalgesia. Moreover, α-fluoromethylhistidine (i.c.v.) abrogated the analgesic effect of histidine. However, histidine treatment initiated later than the first postoperative day (treatment periods included days 2-3, 4-7, and 8-14 PO) did not show an analgesic effect. In addition, histidine treatment initiated immediately, but not 3 days after PSL, inhibited microglial activation and IL-1β upregulation in the lumbar spinal cord, in parallel with its effects on behavioral hypersensitivity. Moreover, the inhibitory effects on pain hypersensitivity and spinal microglial activation were absent in HDC(-/-) mice and IL-1R(-/-) mice. H1 receptor antagonist mepyramine (200 ng/rat i.t. or i.c.), but not H2 receptor antagonist cimetidine (200, 500 ng/rat i.t. or 500 ng/rat i.c.), blocked the effects of histidine on pain behavior and spinal microglia.
  
  
  
  These results demonstrate that central histamine is analgesic within a critical time window in the PSL model of neuropathic pain via histamine H1 receptors. This effect may partly relate to the inhibition of microglial activation and IL-1β production in the spinal cord following nerve injury.
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.|College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Tang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
authors.forename: Ran-Ran
authors.initials: RR
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Lou
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Hou
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
authors.forename: Jia-Xing
authors.initials: JX
authors.lastname: Yue
authors.affiliation: Department of Engineering, School of Medicine, Tohoku University, Aoba-ku, Sendai, 980-8775, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohtsu
authors.affiliation: Department of Basic Medical Science, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China.
authors.forename: Li-Yun
authors.initials: LY
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China. shzhang713@zju.edu.cn.
authors.forename: Shi-Hong
authors.initials: SH
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China. chenzhong@zju.edu.cn.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. chenzhong@zju.edu.cn.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D002927:Cimetidine / Q000494:pharmacology; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006639:Histidine / Q000494:pharmacology / Q000627:therapeutic use*; D006640:Histidine Decarboxylase / Q000172:deficiency / Q000235:genetics; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017288:Pain Threshold / Q000187:drug effects; D011738:Pyrilamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D000700:Analgesics; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D017472:Receptors, Interleukin-1; D006639:Histidine; D002927:Cimetidine; D006640:Histidine Decarboxylase; D011738:Pyrilamine
keywords: Analgesic effect; Central histamine; Histidine; IL-1β; Microglial activation; Neuropathic pain