Presynaptic inhibition of optogenetically identified VGluT3+ sensory fibres by opioids and baclofen.
Presynaptic inhibition of optogenetically identified VGluT3+ sensory fibres by opioids and baclofen.
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DOI：
10.1097/01.j.pain.0000460304.63948.40
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发表时间：
2015-02
期刊：
影响因子：
7.4
通讯作者：
Sandkühler J
中科院分区：
文献类型：
--
作者：
Honsek SD;Seal RP;Sandkühler J
感觉神经纤维的不同子集参与介导机械和热疼痛超敏性。他们也可能对镇痛药有不同的反应。例如，热敏感性C纤维被认为对μ-阿片受体（莫尔）激活做出反应，而机械感受性纤维被认为对δ-阿片受体（DOR）或GABAB受体（GABABR）激活敏感。然而，在感觉纤维的不同亚群上，抑制性神经递质受体的差异性分布存在很大争议。我们现在定量比较阿片类药物和GABABR激动剂巴氯芬对1）囊泡谷氨酸转运蛋白亚型3阳性（VGluT 3+）非伤害性初级传入纤维和2）推定的伤害性C纤维的突触前抑制程度。为了研究VGluT 3+感觉纤维，我们在表达通道视紫红质-2的小鼠脊髓切片背根神经节（DRG）水平用蓝光诱发兴奋性突触后电流。通过电刺激在VGluT 3敲除小鼠中探索推定的伤害性C纤维。莫尔激动剂DAMGO强烈抑制支配I层神经元的VGluT 3+和VGluT 3 − C纤维，但通常对支配II层神经元的纤维影响较小。DOR激动剂SNC 80在任何测试的纤维类型中对突触传递没有任何明显的影响。巴氯芬，在鲜明的对比，强烈抑制所有的纤维种群调查。总之，我们报告了脊髓切片中DRG神经元的光遗传学刺激作为初级传入神经纤维的亚型选择性研究的可行方法。总的来说，不同亚型的感觉纤维的药理学可及性相当重叠，表明莫尔、DOR和GABABR表达在热和机械敏感性纤维之间基本上不分离。
Distinct subsets of sensory nerve fibres are involved in mediating mechanical and thermal pain hypersensitivity. They may also differentially respond to analgesics. Heat-sensitive C-fibres, for example, are thought to respond to µ-opioid receptor (MOR) activation while mechanoreceptive fibres are supposedly sensitive to δ-opioid receptor (DOR) or GABAB receptor (GABABR) activation. The suggested differential distribution of inhibitory neurotransmitter receptors on different subsets of sensory fibres is, however, heavily debated. We now quantitatively compared the degree of presynaptic inhibition exerted by opioids and the GABABR agonist baclofen on 1) vesicular glutamate transporter subtype 3 positive (VGluT3+) non-nociceptive primary afferent fibres and 2) putative nociceptive C-fibres. To investigate VGluT3+ sensory fibres, we evoked excitatory postsynaptic currents with blue light at the level of the dorsal root ganglion (DRG) in spinal cord slices of mice, expressing channelrhodopsin-2. Putative nociceptive C-fibres were explored in VGluT3-knockout mice via electrical stimulation. The MOR agonist DAMGO strongly inhibited both VGluT3+ and VGluT3− C-fibres innervating lamina I neurons but generally had less influence on fibres innervating lamina II neurons. The DOR agonist SNC80 did not have any pronounced effect on synaptic transmission in any fibre type tested. Baclofen, in striking contrast, powerfully inhibited all fibre populations investigated. In summary, we report optogenetic stimulation of DRG neurons in spinal slices as capable approach for the subtype-selective investigation of primary afferent nerve fibres. Overall, the pharmacological accessibility of different subtypes of sensory fibres considerably overlaps, indicating that MOR, DOR and GABABR expression is not substantially segregated between heat and mechanosensitive fibres.
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