Antinociceptive effects of histamine H3 receptor antagonist in the preclinical models of pain in rats and the involvement of central noradrenergic systems
Antinociceptive effects of histamine H3 receptor antagonist in the preclinical models of pain in rats and the involvement of central noradrenergic systems
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DOI：
10.1016/j.brainres.2010.07.083
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发表时间：
2010-10-01
期刊：
影响因子：
2.9
通讯作者：
Brioni, Jorge D.
中科院分区：
文献类型：
--
作者：
Hsieh, Gin C.;Honore, Prisca;Brioni, Jorge D.
组胺H-3受体主要在中枢神经系统中表达，并在多种生理机制中发挥作用。在本研究中，GSK 189254，一种有效的和选择性的H-3拮抗剂，在大鼠临床前疼痛模型的影响进行了表征。全身性GSK 189254产生剂量依赖性功效（ED 50 =0.77 mg/kg i. p.）在单碘乙酸盐（MIA）诱导的骨关节炎（OA）疼痛的大鼠模型中，通过后肢握力评价。使用其他结构不同的H-3拮抗剂进一步证明了H-3受体在调节疼痛感知中的作用。GSK 189254还在指示中枢致敏的大鼠替代模型中显示出功效，即在神经性疼痛的脊神经结扎模型中福尔马林诱导的退缩的2期反应和减弱的触觉异常性疼痛（ED 50 = 1.5mg/kg i. p.）。此外，GSK 189254逆转持续性（CFA）（ED 50 =2.1 mg/kg i.p），而在急性（角叉菜胶）炎性疼痛中无效。当鞘内（i.t.）对于腰脊髓，GSK 189254在缓解OA疼痛方面产生了稳健的效果（ED 50 =0.0027 mg/kg i. t.）。全身性GSK 189254效应被α-肾上腺素能受体拮抗剂酚妥拉明（腹腔注射和腹腔注射）完全逆转但不被阿片受体拮抗剂纳洛酮（i. p.）所抑制。此外，I.T.当与酚妥拉明（i.t.）联合给药时，GSK 189254的作用被消除。这些结果表明，脊髓是H-3拮抗作用的重要部位，其作用可能与去甲肾上腺素能系统的激活有关。我们的数据还提供了支持，选择性H3拮抗剂可能代表一类药物用于治疗疼痛疾病。(C)2010 Elsevier BV保留所有权利。
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.