• Stephen J Medhurst, Sue D Collins, Andy Billinton, Sharon Bingham, Robert G Dalziel, Amanda Brass, Jennifer C Roberts, Andrew D Medhurst, and Iain P Chessell.
• Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, Third Avenue, Harlow, Essex CM19 5AW, UK. stephen.j.medhurst@gsk.com
• Pain. 2008 Aug 15; 138 (1): 61-9.

AbstractSeveral 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 GSK189254 (6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride) and GSK334429 (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 GSK189254 (0.3, 3 and/or 10mg/kg p.o.) and GSK334429 (1, 3 and 10mg/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, GSK189254 (3mg/kg p.o.) and GSK334429 (10mg/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 [(3)H]-GSK189254 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 GSK189254 and GSK334429 may be useful for the treatment of neuropathic pain.

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