Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, School of Medicine, Lubbock, TX, USA.
Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, School of Medicine, Lubbock, TX, USA; Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
Neuropharmacology. 2018 Aug;138:219-231. doi: 10.1016/j.neuropharm.2018.06.015. Epub 2018 Jun 13.
Chronic neuropathic pain is an important healthcare issue with significant emotional components. The amygdala is a brain region involved in pain and emotional-affective states and disorders. The central amygdala output nucleus (CeA) contains small-conductance calcium-activated potassium (SK) channels that can control neuronal activity. A clinically available therapeutic, riluzole can activate SK channels and may have antinociceptive effects through a supraspinal action. We tested the hypothesis that riluzole inhibits neuropathic pain behaviors by inhibiting pain-related changes in CeA neurons, in part at least through SK channel activation.
Brain slice physiology and behavioral assays were done in adult Sprague Dawley rats. Audible and ultrasonic vocalizations and von Frey thresholds were measured in sham and neuropathic rats 4 weeks after left L5 spinal nerve ligation (SNL model). Whole cell patch-clamp recordings of regular firing CeA neurons in brain slices were used to measure synaptic transmission and neuronal excitability.
In brain slices, riluzole increased the SK channel-mediated afterhyperpolarization and synaptic inhibition, but inhibited neuronal excitability through an SK channel independent action. SNL rats had increased vocalizations and decreased withdrawal thresholds compared to sham rats, and intra-CeA administration of riluzole inhibited vocalizations and depression-like behaviors but did not affect withdrawal thresholds. Systemic riluzole administration also inhibited these changes, demonstrating the clinical utility of this strategy. SK channel blockade in the CeA attenuated the inhibitory effects of systemic riluzole on vocalizations, confirming SK channel involvement in these effects.
The results suggest that riluzole has beneficial effects on neuropathic pain behaviors through SK channel dependent and independent mechanisms in the amygdala.
慢性神经性疼痛是一个重要的医疗保健问题，具有显著的情感成分。杏仁核是一个参与疼痛和情感-情感状态和障碍的大脑区域。中央杏仁核输出核（CeA）含有小电导钙激活钾（SK）通道，可控制神经元活动。一种临床可用的治疗药物利鲁唑可以激活 SK 通道，并且可能通过中枢作用产生镇痛作用。我们测试了这样一个假设，即利鲁唑通过抑制 CeA 神经元与疼痛相关的变化来抑制神经性疼痛行为，至少部分是通过 SK 通道的激活。
在成年 Sprague Dawley 大鼠中进行脑片生理学和行为学测定。在左 L5 脊神经结扎（SNL 模型）后 4 周，对假手术和神经性大鼠进行可听和超声发声和 von Frey 阈值测量。使用脑片的常规放电 CeA 神经元全细胞膜片钳记录来测量突触传递和神经元兴奋性。
在脑片中，利鲁唑增加了 SK 通道介导的后超极化和突触抑制，但通过 SK 通道非依赖性作用抑制了神经元兴奋性。与假手术大鼠相比，SNL 大鼠发声增加，退缩阈值降低，而 CeA 内给予利鲁唑抑制发声和抑郁样行为，但不影响退缩阈值。全身给予利鲁唑也抑制了这些变化，证明了这种策略的临床实用性。CeA 中的 SK 通道阻断减弱了全身利鲁唑对发声的抑制作用，证实了 SK 通道参与了这些作用。
这些结果表明，利鲁唑通过杏仁核中的 SK 通道依赖和非依赖机制对神经性疼痛行为具有有益的影响。
