Pain Research Center, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.
Center for Advanced Pain Studies, Department of Neuroscience, University of Texas at Dallas, Richardson, Texas 75080.
J Neurosci. 2022 Jan 19;42(3):350-361. doi: 10.1523/JNEUROSCI.1793-21.2021. Epub 2021 Nov 23.
Highly correlated firing of primary afferent inputs and lamina I projection neurons evokes synaptic long-term potentiation (LTP), a mechanism by which ascending nociceptive transmission can be amplified at the level of the spinal dorsal horn. However, the degree to which neuromodulatory signaling shapes the temporal window governing spike-timing-dependent plasticity (STDP) at sensory synapses onto projection neurons remains unclear. The present study demonstrates that activation of spinal D1/D5 dopamine receptors (D1/D5Rs) creates a highly permissive environment for the production of LTP in male and female adult mouse spinoparabrachial neurons by promoting non-Hebbian plasticity. Bath application of the mixed D1/D5R agonist SKF82958 unmasked LTP at STDP pairing intervals that normally fail to alter synaptic efficacy. Furthermore, during D1/D5R signaling, action potential discharge in projection neurons became dispensable for LTP generation, and primary afferent stimulation alone was sufficient to induce strengthening of sensory synapses. This non-Hebbian LTP was blocked by the D1/D5R antagonist SCH 39166 or genetic deletion of D5R, and required activation of mGluR5 and intracellular Ca release but was independent of NMDAR activation. D1/D5R-enabled non-Hebbian plasticity was observed across multiple neuronal subpopulations in the superficial dorsal horn but was more prevalent in spinoparabrachial neurons than interneurons. Interestingly, the ability of neonatal tissue damage to promote non-Hebbian LTP in adult projection neurons was not observed in D5R knock-out mice. Collectively, these findings suggest that joint spinal D1/D5R and mGluR5 activation can allow unfettered potentiation of sensory synapses onto the output neurons responsible for conveying pain and itch information to the brain. Synaptic LTP in spinal projection neurons has been implicated in the generation of chronic pain. Under normal conditions, plasticity at sensory synapses onto adult mouse spinoparabrachial neurons follows strict Hebbian learning rules, requiring coincident presynaptic and postsynaptic firing. Here, we demonstrate that the activation of spinal D1/D5Rs promotes a switch from Hebbian to non-Hebbian LTP so that primary afferent stimulation alone is sufficient to evoke LTP in the absence of action potential discharge in projection neurons, which required joint activation of mGluR5 and intracellular Ca release but not NMDARs. These results suggest that D1/D5Rs cooperate with mGluR5 receptors in the spinal dorsal horn to powerfully influence the amplification of ascending nociceptive transmission to the brain.
初级传入输入和 I 层投射神经元的高度相关放电引发突触长时程增强（LTP），这是一种在脊髓背角水平上增强上行伤害性传递的机制。然而，神经调质信号在多大程度上塑造了支配投射神经元上感觉突触的尖峰时间依赖可塑性（STDP）的时间窗口尚不清楚。本研究表明，激活脊髓 D1/D5 多巴胺受体（D1/D5R）通过促进非赫布式可塑性，为雄性和雌性成年小鼠脊髓三叉神经传入-臂旁核神经元中 LTP 的产生创造了一个高度许可的环境。混合 D1/D5R 激动剂 SKF82958 的浴应用揭示了在通常无法改变突触效能的 STDP 配对间隔下产生 LTP。此外，在 D1/D5R 信号传递期间，投射神经元的动作电位放电对于 LTP 的产生变得可有可无，而仅刺激初级传入即可诱导感觉突触的增强。这种非赫布式 LTP 被 D1/D5R 拮抗剂 SCH 39166 或 D5R 的基因缺失所阻断，并且需要 mGluR5 的激活和细胞内 Ca 释放，但不依赖于 NMDAR 激活。在脊髓背角浅层的多个神经元亚群中观察到 D1/D5R 使能的非赫布式可塑性，但在脊髓三叉神经传入-臂旁核神经元中比中间神经元更为普遍。有趣的是，在 D5R 敲除小鼠中未观察到新生儿组织损伤促进成年投射神经元中非赫布式 LTP 的能力。总的来说，这些发现表明，脊髓 D1/D5R 和 mGluR5 的联合激活可以允许对负责向大脑传递疼痛和瘙痒信息的输出神经元上的感觉突触进行不受限制的增强。脊髓投射神经元中的突触 LTP 与慢性疼痛的产生有关。在正常情况下，成年小鼠脊髓三叉神经传入-臂旁核神经元上的突触可塑性遵循严格的赫布式学习规则，需要突触前和突触后放电的同时发生。在这里，我们证明，脊髓 D1/D5R 的激活促进了从赫布式到非赫布式 LTP 的转变，因此仅刺激初级传入即可在没有投射神经元动作电位放电的情况下引发 LTP，这需要 mGluR5 和细胞内 Ca 释放的联合激活，但不需要 NMDAR。这些结果表明，D1/D5R 在脊髓背角中与 mGluR5 受体合作，有力地影响了上行伤害性传递到大脑的放大。
