Combinations of intrathecal gamma-amino-butyrate receptor agonists and N-methyl-d-aspartate receptor antagonists in rats with neuropathic spinal cord injury pain.
Combinations of intrathecal gamma-amino-butyrate receptor agonists and N-methyl-d-aspartate receptor antagonists in rats with neuropathic spinal cord injury pain.
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DOI：
10.1016/j.ejphar.2012.03.015
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发表时间：
2012-05-15
影响因子：
5
通讯作者：
Sagen, Jacqueline
中科院分区：
文献类型：
--
作者：
Hama, Aldric;Sagen, Jacqueline
在脊髓损伤(SCI)后观察到的底层皮肤超敏反应是脊髓背角同时失去抑制和兴奋增加。因此，双重药理学方法，增加脊髓γ-氨基丁酸抑制和减少N-甲基-D-天冬氨酸受体介导的兴奋，可能比单独使用任何一种方法都更有利。本研究评价腰椎鞘内注射(I.T.)的抗伤害作用。GABA受体激动剂和NMDA受体拮抗剂在神经病理性脊髓损伤大鼠中的单独和联合应用。在急性胸髓压迫后，大鼠的后爪收缩阈值显著降低，表明低水平的超敏反应。另外，IT。GABAA受体激动剂Muscimol和GABAB受体激动剂巴氯芬表现出剂量依赖性的抗伤害效应，而I.T.NMDA受体拮抗剂氯胺酮和内源性多肽[Ser1]组胺可能是NMDA受体拮抗剂，但均无效。巴氯芬和氯胺酮的组合产生了超加性(协同)的抗伤害作用，而与麝香酚的组合只是相加的。鞘内注射GABA受体拮抗剂CGp 35348可阻断巴氯芬和氯胺酮联合的抗伤害性作用。这些数据表明，单独阻断脊髓NMDA受体不足以改善脊髓损伤的超敏反应，而同时激活脊髓GABAB受体和用氯胺酮阻断NMDA受体的联合方法，可以显著地抑制伤害性感觉。通过在脊柱水平参与不同的疼痛调节系统，联合药物治疗可能是治疗神经病理性脊髓疼痛的有效方法。
Underlying below-level cutaneous hypersensitivity observed following spinal cord injury (SCI) is a concurrent loss of inhibition with an increase in excitation in the spinal dorsal horn. Thus, a dual pharmacological approach, increasing spinal γ-aminobutyrate (GABA) inhibition and decreasing N-methyl-D-aspartate (NMDA) receptor-mediated excitation, could be more beneficial than either approach alone. The current study evaluated the antinociceptive effects of lumbar intrathecal (i.t.) administration of GABA receptor agonists and NMDA receptor antagonists alone and in combination in rats with neuropathic SCI pain. Rats developed markedly decreased hind paw withdrawal thresholds following an acute thoracic spinal cord compression, indicative of below-level hypersensitivity. Separately, i.t. GABAA receptor agonist muscimol and GABAB receptor agonist baclofen demonstrated dose-dependent antinociception, whereas i.t. NMDA receptor antagonist ketamine and the endogenous peptide [Ser1]histogranin, a putative NMDA receptor antagonist, demonstrated no efficacy. The combination of baclofen and ketamine resulted in a supra-additive (synergistic) antinociception whereas the combinations with muscimol were merely additive. Intrathecal pretreatment with the GABAB receptor antagonist CGP 35348 prevented the antinociceptive effect of the baclofen and ketamine combination. The data indicate that blocking spinal NMDA receptors alone is not sufficient to ameliorate SCI hypersensitivity, whereas a combined approach, simultaneous activation of spinal GABAB receptors and NMDA receptors blockade with ketamine, leads to significant antinociception. By engaging diverse pain modulating systems at the spinal level, combination drug treatment may be a useful approach in treating neuropathic SCI pain.
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影响因子：
4.7
作者：
Gwak, Young S.;Hulsebosch, Claire E.
通讯作者：
Hulsebosch, Claire E.
DOI：
10.1523/jneurosci.2428-10.2010
发表时间：
2010-11-03
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bedi SS;Yang Q;Crook RJ;Du J;Wu Z;Fishman HM;Grill RJ;Carlton SM;Walters ET
通讯作者：
Walters ET
影响因子：
2.9
作者：
Eaton, MJ;Martinez, MA;Karmally, S
通讯作者：
Karmally, S
影响因子：
5.3
作者：
Bruce, JC;Oatway, MA;Weaver, LC
通讯作者：
Weaver, LC
影响因子：
7.4
作者：
Carlton SM;Du J;Tan HY;Nesic O;Hargett GL;Bopp AC;Yamani A;Lin Q;Willis WD;Hulsebosch CE
通讯作者：
Hulsebosch CE