Sodium-calcium exchanger-3 regulates pain "wind-up": From human psychophysics to spinal mechanisms.
Sodium-calcium exchanger-3 regulates pain "wind-up": From human psychophysics to spinal mechanisms.
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DOI：
10.1016/j.neuron.2022.05.017
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发表时间：
2022-08-17
期刊：
影响因子：
16.2
通讯作者：
Bennett DL
中科院分区：
文献类型：
--
作者：
Trendafilova T;Adhikari K;Schmid AB;Patel R;Polgár E;Chisholm KI;Middleton SJ;Boyle K;Dickie AC;Semizoglou E;Perez-Sanchez J;Bell AM;Ramirez-Aristeguieta LM;Khoury S;Ivanov A;Wildner H;Ferris E;Chacón-Duque JC;Sokolow S;Saad Boghdady MA;Herchuelz A;Faux P;Poletti G;Gallo C;Rothhammer F;Bedoya G;Zeilhofer HU;Diatchenko L;McMahon SB;Todd AJ;Dickenson AH;Ruiz-Linares A;Bennett DL
重复施加伤害性刺激导致疼痛感知逐渐增加;这种时间总和在临床疼痛障碍中增强并可预测临床疼痛障碍。它的电生理学相关是“发条”，其中背角脊髓神经元增加其对重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，并发现与SLC 8A 3编码的钠钙交换器3型（NCX 3）显著相关。NCX 3在小鼠背角神经元中表达，缺乏NCX 3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压迫性损伤超敏。缺乏NCX 3的背角神经元在重复刺激后表现出细胞内钙增加，钙清除减慢，并增加了发条。此外，病毒介导的NCX 3脊髓表达增强降低了中枢致敏作用。我们的研究强调了Ca 2+外流作为一种潜在的时间总和和持续性疼痛的途径，这可能是适合于治疗靶向。人类疼痛缠绕和NCX 3基因座之间的显著遗传关联NCX 3缺失小鼠在炎症性和神经性疼痛模型中表现出超敏反应NCX 3缺失背角脊髓神经元表现出增加的缠绕和细胞内Ca 2+病毒介导的NCX 3脊髓过表达减少小鼠的疼痛相关行为重复性伤害性刺激增加疼痛感知（缠绕）。Trendafilova等人证明了钠钙交换器NCX 3和人类发条之间的显着遗传关联。缺乏NCX 3的小鼠表现出增加的疼痛相关行为和脊髓过度兴奋性，这是由于Ca 2+清除减慢。NCX 3的脊髓表达增强减少了小鼠的疼痛，这表明了治疗潜力。
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. Significant genetic association between human pain wind-up and the NCX3 locus NCX3 null mice show hypersensitivity in inflammatory and neuropathic pain models NCX3 null dorsal horn spinal neurons show increased wind-up and intracellular Ca2+ Virally mediated spinal overexpression of NCX3 reduces pain-related behavior in mice Repetitive noxious stimuli increase pain perception (wind-up). Trendafilova et al. demonstrate significant genetic association between the sodium-calcium exchanger NCX3 and human wind-up. Mice lacking NCX3 show increased pain-related behavior and spinal hyper-excitability due to slowed Ca2+ clearance. Enhanced spinal expression of NCX3 reduced pain in mice, suggesting therapeutic potential.
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影响因子：
16.6
作者：
Adhikari K;Fuentes-Guajardo M;Quinto-Sánchez M;Mendoza-Revilla J;Camilo Chacón-Duque J;Acuña-Alonzo V;Jaramillo C;Arias W;Lozano RB;Pérez GM;Gómez-Valdés J;Villamil-Ramírez H;Hunemeier T;Ramallo V;Silva de Cerqueira CC;Hurtado M;Villegas V;Granja V;Gallo C;Poletti G;Schuler-Faccini L;Salzano FM;Bortolini MC;Canizales-Quinteros S;Cheeseman M;Rosique J;Bedoya G;Rothhammer F;Headon D;González-José R;Balding D;Ruiz-Linares A
通讯作者：
Ruiz-Linares A
影响因子：
16.2
作者：
Foster, Edmund;Wildner, Hendrik;Tudeau, Laetitia;Haueter, Sabine;Ralvenius, William T.;Jegen, Monika;Johannssen, Helge;Hoesli, Ladina;Haenraets, Karen;Ghanem, Alexander;Conzelmann, Karl-Klaus;Boesl, Michael;Zeilhofer, Hanns Ulrich
通讯作者：
Zeilhofer, Hanns Ulrich
影响因子：
16.2
作者：
Dawes JM;Weir GA;Middleton SJ;Patel R;Chisholm KI;Pettingill P;Peck LJ;Sheridan J;Shakir A;Jacobson L;Gutierrez-Mecinas M;Galino J;Walcher J;Kühnemund J;Kuehn H;Sanna MD;Lang B;Clark AJ;Themistocleous AC;Iwagaki N;West SJ;Werynska K;Carroll L;Trendafilova T;Menassa DA;Giannoccaro MP;Coutinho E;Cervellini I;Tewari D;Buckley C;Leite MI;Wildner H;Zeilhofer HU;Peles E;Todd AJ;McMahon SB;Dickenson AH;Lewin GR;Vincent A;Bennett DL
通讯作者：
Bennett DL
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
4.6
作者：
Bakshi A;Zhu Z;Vinkhuyzen AA;Hill WD;McRae AF;Visscher PM;Yang J
通讯作者：
Yang J