The
histamine H(3) receptor is predominantly expressed in the central nervous system and plays a role in diverse physiological mechanisms. In the present study, the effects of
GSK189254, a potent and selective H(3) antagonist, were characterized in preclinical
pain models in rats. Systemic
GSK189254 produced dose-dependent efficacy (ED(50)=0.77 mg/kg i.p.) in a rat model of monoiodoacetate (MIA) induced osteoarthritic (OA)
pain as evaluated by hindlimb grip force. The role of H(3) receptors in regulating pain perception was further demonstrated using other structurally distinct H(3) antagonists.
GSK189254 also displayed efficacy in a rat surrogate model indicative of central sensitization, namely phase 2 response of
formalin-induced flinching, and attenuated
tactile allodynia in the spinal nerve
ligation model of
neuropathic pain (ED(50)=1.5mg/kg i.p.). In addition,
GSK189254 reversed persistent (CFA) (ED(50)=2.1mg/kg i.p,), whereas was ineffective in acute (
carrageenan) inflammatory
pain. When administered intrathecally (i.t.) to the lumbar spinal cord,
GSK189254 produced robust effects in relieving the OA
pain (ED(50)=0.0027 mg/kg i.t.). The systemic
GSK189254 effect was completely reversed by the
alpha-adrenergic receptor antagonist
phentolamine (i.p. and i.t.) but not by the
opioid receptor antagonist naloxone (i.p.). Furthermore, the i.t.
GSK189254 effect was abolished when co-administered with
phentolamine (i.t.). These results suggest that the spinal cord is an important site of action for H(3) antagonism and the effect can be associated with activation of the noradrenergic system. Our data also provide support that selective H(3) antagonists may represent a class of agents for the treatment of
pain disorders.