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Author Notes:

Correspondence: Claudia R Morris, Division of Pediatric Emergency Medicine, Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive NE, W458, Atlanta, GA 30322, USA, Tel +1 404 727 5500, Email: claudia.r.morris@emory.edu; Email: claudiamorris@comcast.net

The authors report no other conflicts of interest in this work.


Research Funding:

Nitya Bakshi has received funding from the Sickle Cell Disease Association of America Research Scholar Program.

Claudia R Morris, is the inventor or coinventor of several Children’s Hospital and Research Center Oakland patents/patent-pending applications that include biomarkers of cardiovascular disease related to arginine bioavailability, is an inventor of an Emory University School of Medicine patent application for a nutritional supplement, is a consultant for Pfizer, NourishLife, LLC, and Calithera Biosciences, Inc., and has received research support from MAST Therapeutics, the United States Food and Drug Administration, and the National Institutes of Health.


  • arginine
  • arginase
  • sickle cell disease
  • pain
  • global arginine bioavailability ratio
  • nitric oxide

The role of the arginine metabolome in pain: Implications for sickle cell disease


Journal Title:

Journal of Pain Research


Volume 9


, Pages 167-175

Type of Work:

Article | Final Publisher PDF


Sickle cell disease (SCD) is the most common hemoglobinopathy in the US, affecting approximately 100,000 individuals in the US and millions worldwide. Pain is the hallmark of SCD, and a subset of patients experience pain virtually all of the time. Of interest, the arginine metabolome is associated with several pain mechanisms highlighted in this review. Since SCD is an arginine deficiency syndrome, the contribution of the arginine metabolome to acute and chronic pain in SCD is a topic in need of further attention. Normal arginine metabolism is impaired in SCD through various mechanisms that contribute to endothelial dysfunction, vaso-occlusion, pulmonary complications, risk of leg ulcers, and early mortality. Arginine is a semiessential amino acid that serves as a substrate for protein synthesis and is the precursor to nitric oxide (NO), polyamines, proline, glutamate, creatine, and agmatine. Since arginine is involved in multiple metabolic processes, a deficiency of this amino acid has the potential to disrupt many cellular and organ functions. NO is a potent vasodilator that is depleted in SCD and may contribute to vaso-occlusive pain. As the obligate substrate for NO production, arginine also plays a mechanistic role in SCD-related pain, although its contribution to pain pathways likely extends beyond NO. Low global arginine bioavailability is associated with pain severity in both adults and children with SCD as well as other non-SCD pain syndromes. Preliminary clinical studies of arginine therapy in SCD demonstrate efficacy in treating acute vaso-occlusive pain, as well as leg ulcers and pulmonary hypertension. Restoration of arginine bioavailability through exogenous supplementation of arginine is, therefore, a promising therapeutic target. Phase II clinical trials of arginine therapy for sickle-related pain are underway and a Phase III randomized controlled trial is anticipated in the near future.

Copyright information:

© 2016 Bakshi and Morris. This work is published and licensed by Dove Medical Press Limited

This is an Open Access work distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/).

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