Peripheral nerve injury and gabapentin, but not their combination, impair attentional behavior via direct effects on noradrenergic signaling in the brain.
Peripheral nerve injury and gabapentin, but not their combination, impair attentional behavior via direct effects on noradrenergic signaling in the brain.
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DOI：
10.1016/j.pain.2014.05.014
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发表时间：
2014-10
期刊：
影响因子：
7.4
通讯作者：
Hayashida K
中科院分区：
文献类型：
--
作者：
Suto T;Eisenach JC;Hayashida K
外周神经损伤后的慢性疼痛通常伴随着前额皮质（PFC）相关认知功能的降低，这是由源自蓝斑（LC）的输出神经释放的去甲肾上腺素调节的。L5-L6脊髓神经结扎（SNL）增加了PFC微透析液中去甲肾上腺素的组织含量和细胞外浓度，并损害了新物体识别测试中的注意力水平。通常用于治疗慢性疼痛的全身加巴喷丁，在正常动物中损害了新的物体识别任务，而在SNL动物中没有。因此，加巴喷丁增加了正常动物LC神经元中c-fos的表达和PFC中去甲肾上腺素的释放，但在SNL动物中，加巴喷丁没有增加PFC外突LC神经元中c-fos的表达，也没有增加PFC中去甲肾上腺素的释放。相反，局部灌注加巴喷丁在体内和体外PFC突触体中减少了去甲肾上腺素的释放。通过腹腔注射α1-肾上腺素受体拮抗剂吡唑嗪，可以逆转SNL和加巴喷丁诱导的新物体识别任务障碍。这些结果表明，由神经损伤或加巴喷丁引起的去甲肾上腺素能张力升高可能通过α - 1肾上腺素受体介导的机制损害PFC功能，加巴喷丁对PFC中去甲肾上腺素释放的净效应可能取决于不同部位的相反作用，神经损伤选择性地损害了LC中PFC投射神经元对加巴喷丁的反应。
Chronic pain following peripheral nerve damage is often accompanied by a reduction in prefrontal cortex (PFC)-related cognitive functions, which are regulated by noradrenaline, released from efferents originating in the locus coeruleus (LC). L5-L6 spinal nerve ligation (SNL) increased tissue content and extracellular concentrations of noradrenaline in microdialysates from the PFC, and impaired attentional level in the novel object recognition test. Systemic gabapentin, commonly used to treat chronic pain, impaired the novel object recognition task in normal, but not SNL animals. Accordingly, gabapentin increased c-fos expression in LC neurons and noradrenaline release in the PFC in normal animals, but in SNL animals, gabapentin failed to increase c-fos expression in LC neurons projecting to the PFC and failed to increase noradrenaline release in the PFC. In contrast, locally perfused gabapentin reduced noradrenaline release in the PFC in vivo and in PFC synaptosomes in vitro. SNL- and gabapentin-induced impairment of novel object recognition task was reversed by intraperitoneal injection of the α1-adrenoceptor antagonist prazosin. These results suggest that increase in noradrenergic tone, induced by nerve injury or gabapentin, impairs PFC functions possibly via α1-adrenoceptor-mediated mechanisms, that the net effect of gabapentin on noradrenaline release in the PFC would depend on sometimes opposing actions at different sites, and that nerve injury selectively impairs the response to gabapentin in PFC projecting neurons in the LC.
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