4-bromopropofol decreases action potential generation in spinal neurons by inducing a glycine receptor-mediated tonic conductance.
4-bromopropofol decreases action potential generation in spinal neurons by inducing a glycine receptor-mediated tonic conductance.
复制标题
4-bromopropofol 通过诱导甘氨酸受体介导的强直电导来减少脊髓神经元动作电位的产生。
DOI：
10.1111/bph.12880
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发表时间：
2014
影响因子：
7.3
通讯作者：
Eckle VS
中科院分区：
文献类型：
--
作者：
Eckle VS
背景和目的脊髓士的宁敏感性甘氨酸受体功能受损导致慢性疼痛状态和运动障碍。因此，甘氨酸受体的活性增加应有助于治疗此类疾病。虽然缺乏具有高选择性的靶向甘氨酸受体的化合物，但丙泊酚的卤代类似物最近被认为是潜在的候选物。因此，我们想知道4-溴丙泊酚是否通过促进甘氨酸受体依赖性抑制来减弱脊髓神经元的兴奋性。实验方法亚麻醉浓度的丙泊酚和4-溴丙泊酚的作用在小鼠脊髓组织培养物中进行了研究。通过细胞外多单位记录监测药物诱导的动作电位放电变化。对GABA A和甘氨酸受体介导的抑制的影响通过全细胞电压钳recording.Key ResultsLow浓度的4-溴丙泊酚（50 nM）减少腹角神经元的动作电位活动约30%，与假处理切片相比。士的宁（1 μM）可完全消除这种作用。在电压钳位神经元中，4-溴丙泊酚激活甘氨酸受体，产生65 ± 10 pA的强直电流，而GABAA-和甘氨酸受体介导的突触传递保持不受影响.Conclusions and ImplicationsThe最高甘氨酸水平在中枢神经系统中发现在脊髓腹角，一个区域介导疼痛诱导的运动反射和参与肌张力的控制。4-溴异丙酚可以作为开发用于治疗腰痛的非镇静剂、非成瘾性肌肉松弛剂和镇痛剂的起点。
Background and PurposeImpaired function of spinal strychnine‐sensitive glycine receptors gives rise to chronic pain states and movement disorders. Therefore, increased activity of glycine receptors should help to treat such disorders. Although compounds targeting glycine receptors with a high selectivity are lacking, halogenated analogues of propofol have recently been considered as potential candidates. Therefore we asked whether 4‐bromopropofol attenuated the excitability of spinal neurons by promoting glycine receptor‐dependent inhibition.Experimental ApproachThe actions of sub‐anaesthetic concentrations of propofol and 4‐bromopropofol were investigated in spinal tissue cultures prepared from mice. Drug‐induced alterations in action potential firing were monitored by extracellular multi‐unit recordings. The effects on GABAAand glycine receptor‐mediated inhibition were quantified by whole‐cell voltage‐clamp recordings.Key ResultsLow concentrations of 4‐bromopropofol (50 nM) reduced action potential activity of ventral horn neurons by about 30%, compared with sham‐treated slices. This effect was completely abolished by strychnine (1 μM). In voltage‐clamped neurons, 4‐bromopropofol activated glycine receptors, generating a tonic current of 65 ± 10 pA, while GABAA‐ and glycine receptor‐mediated synaptic transmission remained unaffected.Conclusions and ImplicationsThe highest glycine levels in the CNS are found in the ventral horn of the spinal cord, a region mediating pain‐induced motor reflexes and participating in the control of muscle tone. 4‐Bromopropofol may serve as a starting point for the development of non‐sedative, non‐addictive, muscle relaxants and analgesics to be used to treat low back pain.