Endocannabinoid-dependent plasticity at spinal nociceptor synapses
Endocannabinoid-dependent plasticity at spinal nociceptor synapses
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DOI：
10.1113/jphysiol.2012.234229
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发表时间：
2012-10-01
影响因子：
5.5
通讯作者：
Zeilhofer, Hanns Ulrich
中科院分区：
文献类型：
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作者：
Kato, Ako;Punnakkal, Pradeep;Zeilhofer, Hanns Ulrich
关键点 初级伤害感受器和二级背角神经元之间的突触可塑性在疼痛和镇痛中发挥关键作用 NMDA 受体对这些突触的长期增强和长期抑制的贡献之前已被证明，但对于内源性大麻素和大麻素 (CB)1 受体的可能作用知之甚少。在这里，我们表明，位于初级伤害感受器脊髓末端的 CB1 受体对这些突触处的 NMDA 受体独立形式的长期抑制至关重要，这需要同时进行突触前和突触后活动。在单独存在突触前刺激的情况下，通过应用 CB1 受体激动剂也可以获得类似的伤害性信号传递的持久抑制。这些发现确定了脊髓伤害感受器突触的一种以前未知的长期抑制形式，这对于我们理解与疼痛相关的神经可塑性和 CB1 受体激动剂的镇痛作用可能很重要。摘要 初级伤害感受器和二级背角神经元之间脊髓突触的神经塑性变化在疼痛和镇痛中发挥着关键作用。这些突触的 NMDA 受体依赖性长期可塑性形式已被广泛研究，但人们对内源性大麻素系统的可能贡献知之甚少。在这里，我们讨论了大麻素 (CB)1 受体在这些突触的活动依赖性可塑性中的作用。我们报告说，在野生型小鼠的绝大多数（90%）记录中，对高阈值初级感觉神经纤维的条件低频刺激与突触后神经元的去极化相结合，引起了约 40% 的兴奋性突触传递的强烈长期抑制（LTD）。当从整体或伤害感受器特异性 CB1 受体缺陷小鼠（CB1-/- 小鼠和 sns-CB1-/- 小鼠）进行记录时，表现出 LTD 的神经元部分大幅减少至约 25%。因此，CB1受体拮抗剂AM 251可在类似程度上预防LTD，并通过CB1受体的药理激活来模拟LTD。在 EPSC 刺激阈值特别高的神经元子集中，我们进一步发现 CB1-/- 和 sns-CB1-/- 小鼠中 CB1 受体的缺失将对配对条件刺激方案的反应从 LTD 转变为长时程增强 (LTP)。我们的结果将 CB1 受体依赖性 LTD 确定为脊髓伤害感受器中以前未知的突触可塑性形式。他们进一步表明，预防 LTP 可能是初级伤害感受器中 CB1 受体迄今为止未知的第二个功能。这两项发现可能对我们理解内源性疼痛控制机制和大麻素受体激动剂引起的镇痛具有重要意义。
Key points Synaptic plasticity between primary nociceptors and second order dorsal horn neurons serves key roles in pain and analgesia A contribution of NMDA receptors to long-term potentiation and long-term depression at these synapses has been demonstrated before, but much less is known about a possible role of endocannabinoids and cannabinoid (CB)1 receptors. Here we show that CB1 receptors residing on the spinal terminals of primary nociceptors critically contribute to an NMDA receptor-independent form of long-term depression at these synapses, which requires simultaneous pre- and postsynaptic activity. A similar long-lasting depression of nociceptive signal transmission can also be obtained with application of CB1 receptor agonists in the presence of presynaptic stimulation alone. These findings identify a previously unknown form of long-term depression at spinal nociceptor synapses, which may be important for our understanding of pain-related neural plasticity and analgesic actions of CB1 receptor agonists. Abstract Neuroplastic changes at the spinal synapses between primary nociceptors and second order dorsal horn neurons play key roles in pain and analgesia. NMDA receptor-dependent forms of long-term plasticity have been studied extensively at these synapses, but little is known about possible contributions of the endocannabinoid system. Here, we addressed the role of cannabinoid (CB)1 receptors in activity-dependent plasticity at these synapses. We report that conditional low-frequency stimulation of high-threshold primary sensory nerve fibres paired with depolarisation of the postsynaptic neuron evoked robust long-term depression (LTD) of excitatory synaptic transmission by about 40% in the vast majority (90%) of recordings made in wild-type mice. When recordings were made from global or nociceptor-specific CB1 receptor-deficient mice (CB1-/- mice and sns-CB1-/- mice), the portion of neurons exhibiting LTD was strongly reduced to about 25%. Accordingly, LTD was prevented to a similar extent by the CB1 receptor antagonist AM 251 and mimicked by pharmacological activation of CB1 receptors. In a subset of neurons with EPSCs of particularly high stimulation thresholds, we furthermore found that the absence of CB1 receptors in CB1-/- and sns-CB1-/- mice converted the response to the paired conditioning stimulation protocol from LTD to long-term potentiation (LTP). Our results identify CB1 receptor-dependent LTD as a form of synaptic plasticity previously unknown in spinal nociceptors. They furthermore suggest that prevention of LTP may be a second hitherto unknown function of CB1 receptors in primary nociceptors. Both findings may have important implications for our understanding of endogenous pain control mechanisms and of analgesia evoked by cannabinoid receptor agonists.