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Novel histamine H3 receptor antagonists GSK189254 and GSK334429 are efficacious in surgically-induced and virally-induced rat models of neuropathic pain

2008; Lippincott Williams & Wilkins; Volume: 138; Issue: 1 Linguagem: Inglês

10.1016/j.pain.2007.11.006

1872-6623

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

Allergic Rhinitis and Sensitization

Several studies have implicated a potential role for histamine H3 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 H3 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 10 mg/kg p.o.) and GSK334429 (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, GSK189254 (3 mg/kg p.o.) and GSK334429 (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 H3 antagonists using autoradiography. Specific binding to H3 receptors was demonstrated with [3H]-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 H3 receptors in pain processing. In conclusion, we have shown for the first time that chronic oral administration of selective H3 antagonists is effective in reversing neuropathic hypersensitivity in disease-related models, and that specific H3 receptor binding sites are present in the human DRG and dorsal horn of the spinal cord. These data suggest that H3 antagonists such as GSK189254 and GSK334429 may be useful for the treatment of neuropathic pain.