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.
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