Endothelin type A receptors mediate pain in a mouse model of sickle cell disease

• Published in: Haematologica (Roma) 2018-07, Vol.103 (7), p.1124-1135
• Main Authors: Lutz, Brianna Marie, Wu, Shaogen, Gu, Xiyao, Atianjoh, Fidelis E, Li, Zhen, Fox, Brandon M, Pollock, David M, Tao, Yuan-Xiang
• Format: Article
• Language: English
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2017.187013

Sickle cell disease is associated with acute painful episodes and chronic intractable pain. Endothelin-1, a known pain inducer, is elevated in the blood plasma of both sickle cell patients and mouse models of sickle cell disease. We show here that the levels of endothelin-1 and its endothelin type A receptor are increased in the dorsal root ganglia of a mouse model of sickle cell disease. Pharmacologic inhibition or neuron-specific knockdown of endothelin type A receptors in primary sensory neurons of dorsal root ganglia alleviated basal and post-hypoxia evoked pain hypersensitivities in sickle cell mice. Mechanistically, endothelin type A receptors contribute to sickle cell disease-associated pain likely through the activation of NF-κB-induced Nav1.8 channel upregulation in primary sensory neurons of sickle cell mice. Our findings suggest that endothelin type A receptor is a potential target for the management of sickle cell disease-associated pain, although this expectation needs to be further verified in clinical settings.