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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)61-69
Number of pages9
JournalPain
Volume138
Issue number1
DOIs
Publication statusPublished - 15 Aug 2008

Keywords

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

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