Page 46 - Haematologica July

Ferrata Storti Foundation
Red Cell Biology & its Disorders
Endothelin type A receptors mediate pain in a mouse model of sickle cell disease
Brianna Marie Lutz,1,2 Shaogen Wu,1 Xiyao Gu,1 Fidelis E. Atianjoh,1,3 Zhen Li,1 Brandon M. Fox,4 David M. Pollock4 and Yuan-Xiang Tao1,2,5
Haematologica 2018 Volume 103(7):1124-1135
1Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA; 2Rutgers Graduate School of Biomedical Sciences, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA; 3Intensive Care Unit, MedStar Southern Maryland Hospital Center, Clinton, MD, USA; 4Cardio-Renal Physiology and Medicine, Department of Medicine, University of
5
Alabama at Birmingham, AL, USA and Neuroscience Research Institute, Zhengzhou
University Academy of Medical Sciences, Henan, China
ABSTRACT
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 endothe- lin-1 and its endothelin type A receptor are increased in the dorsal root ganglia of a mouse model of sickle cell disease. Pharmacologic inhibi- tion 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.
Introduction
Sickle cell disease (SCD) results from an amino acid substitution in the β globin chain of the oxygen carrying molecule, hemoglobin.1 Approximately 100,000 Americans currently suffer from SCD, and over 80,000 SCD related hospitaliza- tions occur annually resulting in over 450 million dollars in healthcare costs.2 Much of these healthcare costs and hospitalizations stem from acute vaso-occlusive episodes in which patients often report extreme pain.3 Pain is a hallmark of SCD and correlates with morbidity and disease severity.4 In addition to acute painful episodes, some SCD patients report persistent/chronic pain.5 Treatment for SCD- associated pain includes pain medications such as opioids, but pain relief may remain inadequate for many SCD patients. Additionally, repeated and/or pro- longed administration of these drugs has potential side effects.6 Understanding the causes of pain in SCD may bring forward new and more efficient therapeutic strategies for the management of SCD pain.
Endothelin-1 (ET-1) is a 21 amino acid peptide released from endothelial cells, immune cells, and neurons.7 ET-1 binds to endothelin type A (ETA) and endothelin type B (ETB) G-protein coupled receptors.7 Classically, ET-1 acts as a vaso-constric- tor, but recent studies have shown that ET-1 can also induce pain in humans and rodents.8,9 In the dorsal root ganglia (DRG), ETA receptors are expressed predomi- nantly in the primary sensory neurons, while ETB receptors are detected in glial cells.10 Blocking ETA receptors attenuates ET-1-induced nerve fiber activation and pain behavior in rodents.7,11,12 ET-1-induced activation of the ETA receptor has been found to increase intracellular calcium release, potentiate transient receptor poten- tial vanilloid 1 current, and alter the functioning of tetrodotoxin-resistant (TTX-R) sodium channels in DRG neurons,8 but detailed mechanisms of how ET-1 induces pain are not fully understood.
Correspondence:
yt211@njms.rutgers.edu
Received: December 21, 2017. Accepted: March 13, 2018. Pre-published: March 15, 2018.
doi:10.3324/haematol.2017.187013
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/7/1124
©2018 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
1124
haematologica | 2018; 103(7)
ARTICLE