Antinociceptive effects of histamine H3 receptor antagonist in the preclinical models of pain in rats and the involvement of central noradrenergic systems

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 (ED50=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 forrnalin-induced flinching, and attenuated tactile allodynia in the spinal nerve ligation model of neuropathic pain (ED50=1.5 mg/kg i.p.). In addition, GSK189254 reversed persistent (CFA) (ED50=2.1 mg/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 (ED50=0.0027 mg/kg i.t.). The systemic GSK189254 effect was completely reversed by the a-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 H3 antagonists may represent a class of agents for the treatment of pain disorders. (C) 2010 Elsevier B.V. All rights reserved.