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Sodium-calcium exchanger-3 regulates pain “wind-up”: From human psychophysics to spinal mechanisms
Neuron ( IF 16.2 ) Pub Date : 2022-06-14 , DOI: 10.1016/j.neuron.2022.05.017
Teodora Trendafilova 1 , Kaustubh Adhikari 2 , Annina B Schmid 1 , Ryan Patel 3 , Erika Polgár 4 , Kim I Chisholm 5 , Steven J Middleton 1 , Kieran Boyle 4 , Allen C Dickie 4 , Evangelia Semizoglou 5 , Jimena Perez-Sanchez 1 , Andrew M Bell 4 , Luis Miguel Ramirez-Aristeguieta 6 , Samar Khoury 7 , Aleksandar Ivanov 8 , Hendrik Wildner 9 , Eleanor Ferris 1 , Juan-Camilo Chacón-Duque 10 , Sophie Sokolow 11 , Mohamed A Saad Boghdady 1 , André Herchuelz 12 , Pierre Faux 13 , Giovanni Poletti 14 , Carla Gallo 14 , Francisco Rothhammer 15 , Gabriel Bedoya 16 , Hanns Ulrich Zeilhofer 17 , Luda Diatchenko 7 , Stephen B McMahon 5 , Andrew J Todd 4 , Anthony H Dickenson 3 , Andres Ruiz-Linares 18 , David L Bennett 1
Affiliation  

Repeated application of noxious stimuli leads to a progressively increased pain perception; this temporal summation is enhanced in and predictive of clinical pain disorders. Its electrophysiological correlate is “wind-up,” in which dorsal horn spinal neurons increase their response to repeated nociceptor stimulation. To understand the genetic basis of temporal summation, we undertook a GWAS of wind-up in healthy human volunteers and found significant association with SLC8A3 encoding sodium-calcium exchanger type 3 (NCX3). NCX3 was expressed in mouse dorsal horn neurons, and mice lacking NCX3 showed normal, acute pain but hypersensitivity to the second phase of the formalin test and chronic constriction injury. Dorsal horn neurons lacking NCX3 showed increased intracellular calcium following repetitive stimulation, slowed calcium clearance, and increased wind-up. Moreover, virally mediated enhanced spinal expression of NCX3 reduced central sensitization. Our study highlights Ca2+ efflux as a pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting.



中文翻译:

钠钙交换剂 3 调节疼痛“结束”:从人类心理物理学到脊柱机制

反复施加有害刺激会导致疼痛感逐渐增加;这种时间总和在临床疼痛障碍中得到了增强和预测。它的电生理相关性是“发条”,其中背角脊髓神经元增加了它们对反复伤害感受器刺激的反应。为了了解时间总和的遗传基础,我们在健康人类志愿者中进行了 GWAS,发现与编码钠钙交换剂 3 型 ( NCX3 )的SLC8A3显着相关。NCX3在小鼠背角神经元中表达,而缺乏NCX3的小鼠表现出正常的急性疼痛,但对福尔马林试验的第二阶段和慢性收缩损伤过敏。缺乏NCX3的背角神经元在重复刺激后表现出细胞内钙增加、钙清除速度减慢和缠绕增加。此外,病毒介导的NCX3增强的脊髓表达降低了中枢敏感性。我们的研究强调 Ca 2+流出是时间总和和持续性疼痛的潜在途径,这可能适用于治疗靶向。

更新日期:2022-06-14
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