Novel histamine H 3 receptor antagonists GSK189254 and GSK334429 are efficacious in surgically-induced and virally-induced rat models of neuropathic pain

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 GSK189254 (6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-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-1 H-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 H 3 antagonists using autoradiography. Specific binding to H 3 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 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.