The role of the arginine metabolome in pain: implications for sickle cell disease
Nitya Bakshi,1–2 Claudia R Morris3–6 1Division of Pediatric Hematology-Oncology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; 2Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA, USA; 3Division of P...
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2016-03-01
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| Series: | Journal of Pain Research |
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| Online Access: | https://www.dovepress.com/the-role-of-the-arginine-metabolome-in-pain-implications-for-sickle-ce-peer-reviewed-article-JPR |
| _version_ | 1819040072441266176 |
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| author | Bakshi N Morris CR |
| author_facet | Bakshi N Morris CR |
| author_sort | Bakshi N |
| collection | DOAJ |
| description | Nitya Bakshi,1–2 Claudia R Morris3–6 1Division of Pediatric Hematology-Oncology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; 2Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA, USA; 3Division of Pediatric Emergency Medicine, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; 4Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, USA; 5Emory-Children’s Center for Cystic Fibrosis and Airways Disease Research, Emory University School of Medicine, Atlanta, GA, USA; 6Pediatric Emergency Medicine, Children’s Healthcare of Atlanta, Atlanta, GA, USA Abstract: 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. Keywords: arginine, arginase, sickle cell disease, pain, global arginine bioavailability ratio, nitric oxide |
| first_indexed | 2024-12-21T09:03:17Z |
| format | Article |
| id | doaj.art-eb440627981849dba7573fba355e76cb |
| institution | Directory Open Access Journal |
| issn | 1178-7090 |
| language | English |
| last_indexed | 2024-12-21T09:03:17Z |
| publishDate | 2016-03-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Journal of Pain Research |
| spelling | doaj.art-eb440627981849dba7573fba355e76cb2022-12-21T19:09:26ZengDove Medical PressJournal of Pain Research1178-70902016-03-012016Issue 116717526217The role of the arginine metabolome in pain: implications for sickle cell diseaseBakshi NMorris CRNitya Bakshi,1–2 Claudia R Morris3–6 1Division of Pediatric Hematology-Oncology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; 2Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA, USA; 3Division of Pediatric Emergency Medicine, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; 4Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, USA; 5Emory-Children’s Center for Cystic Fibrosis and Airways Disease Research, Emory University School of Medicine, Atlanta, GA, USA; 6Pediatric Emergency Medicine, Children’s Healthcare of Atlanta, Atlanta, GA, USA Abstract: 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. Keywords: arginine, arginase, sickle cell disease, pain, global arginine bioavailability ratio, nitric oxidehttps://www.dovepress.com/the-role-of-the-arginine-metabolome-in-pain-implications-for-sickle-ce-peer-reviewed-article-JPRSickle Cell Disease Vaso-occlusive pain episodes L-arginine Global arginine bioavailability ratio (GABR) Arginase Nitric Oxide |
| spellingShingle | Bakshi N Morris CR The role of the arginine metabolome in pain: implications for sickle cell disease Journal of Pain Research Sickle Cell Disease Vaso-occlusive pain episodes L-arginine Global arginine bioavailability ratio (GABR) Arginase Nitric Oxide |
| title | The role of the arginine metabolome in pain: implications for sickle cell disease |
| title_full | The role of the arginine metabolome in pain: implications for sickle cell disease |
| title_fullStr | The role of the arginine metabolome in pain: implications for sickle cell disease |
| title_full_unstemmed | The role of the arginine metabolome in pain: implications for sickle cell disease |
| title_short | The role of the arginine metabolome in pain: implications for sickle cell disease |
| title_sort | role of the arginine metabolome in pain implications for sickle cell disease |
| topic | Sickle Cell Disease Vaso-occlusive pain episodes L-arginine Global arginine bioavailability ratio (GABR) Arginase Nitric Oxide |
| url | https://www.dovepress.com/the-role-of-the-arginine-metabolome-in-pain-implications-for-sickle-ce-peer-reviewed-article-JPR |
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