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Novel histamine H-3 receptor antagonists GSK 189254 and GSK 334429 are efficacious in surgically-induced and virally-induced rat models of neuropathic pain

Research output: Contribution to journalArticle

  • Stephen J. Medhurst
  • Sue D. Collins
  • Andy Billinton
  • Sharon Bingham
  • Robert G. Dalziel
  • Amanda Brass
  • Jennifer C. Roberts
  • Andrew D. Medhurst
  • Iain P. Chessell

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Original languageEnglish
Pages (from-to)61-69
Number of pages9
Issue number1
Publication statusPublished - 15 Aug 2008


Several studies have implicated a potential role for histamine H-3 receptors in pain processing, although the data are somewhat conflicting. in the present study we investigated the effects of the novel potent and highly selective H-3 receptor antagonists GSK 189254 (6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride) and GSK 334429 (1-(1-methylethyl)-4-({1-[6-(trifluoromethyl)-3-pyridinyl]-4-piperidinyl}carbonyl)hexahydro-1H-1,4-diazepine) in two rat models of neuropathic pain, namely the chronic constriction injury (CCI) model and the varicella-zoster virus (VZV) model. Both GSK 189254 (0.3, 3 and/or 10 mg/kg p.o.) and GSK 334429 (1, 3 and 10 mg/kg p.o.) significantly reversed the CCI-induced decrease in paw withdrawal threshold (PWT) measured using an analgesymeter and/or von Frey hairs. In addition, GSK 189254 (3 mg/kg p.o.) and GSK 334429 (10 mg/kg p.o.) both reversed the VZV-induced decrease in PWT using von Frey hairs. We also investigated the potential site of action of this analgesic effect of H-3 antagonists using autoradiography. Specific binding to H-3 receptors was demonstrated with [H-3]-GSK 189254 in the dorsal horn of the human and rat spinal cord, and in human dorsal root ganglion (DRG), consistent with the potential involvement of H-3 receptors in pain processing. In conclusion, we have shown for the first time that chronic oral administration of selective H-3 antagonists is effective in reversing neuropathic hypersensitivity in disease-related models, and that specific H-3 receptor binding sites are present in the human DRG and dorsal horn of the spinal cord. These data suggest that H-3 antagonists such as GSK 189254 and GSK 334429 may be useful for the treatment of neuropathic pain.

    Research areas

  • Histamine H3 receptor, Chronic constriction injury , Varicella-zoster virus, Neuropathic pain, Allodynia, Hyperalgesia

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