Journal Article Research Support, N.I.H., Extramural Epublish 12 citations
PubMed: 35615929 DOI: 10.3324/haematol.2021.280460
Inhibition of DAGLβ as a therapeutic target for pain in sickle cell disease.
Haematologica 108(3):859-869
Authors: Iryna A Khasabova, Jacob Gable, Malcolm Johns, Sergey G Khasabov, Alexander E Kalyuzhny, Mikhail Y Golovko, Svetlana A Golovko, Stacy Kiven, Kalpna Gupta, Virginia S Seybold, Donald A Simone
Affiliations
- Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN.
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN.
- Department of Anesthesiology, University of Minnesota, Minneapolis, MN.
- Department of Neuroscience, University of Minnesota, Minneapolis, MN.
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND.
- Hematology/Oncology, Department of Medicine, University of California Irvine, Irvine, CA.
- Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN.
Abstract
Sickle cell disease (SCD) is the most common inherited disease. Pain is a key morbidity of SCD and opioids are the main treatment but their side effects emphasize the need for new analgesic approaches. Humanized transgenic mouse models have been instructive in understanding the pathobiology of SCD and mechanisms of pain. Homozygous (HbSS) Berkley mice express >99% human sickle hemoglobin and several features of clinical SCD including hyperalgesia. Previously, we reported that the endocannabinoid 2-arachidonoylglycerol (2-AG) is a precursor of the pro-nociceptive mediator prostaglandin E2-glyceryl ester (PGE2-G) which contributes to hyperalgesia in SCD. We now demonstrate the causal role of 2-AG in hyperalgesia in sickle mice. Hyperalgesia in HbSS mice correlated with elevated levels of 2-AG in plasma, its synthesizing enzyme diacylglycerol lipase β (DAGLβ) in blood cells, and with elevated levels of PGE2 and PGE2-G, pronociceptive derivatives of 2-AG. A single intravenous injection of 2-AG produced hyperalgesia in non-hyperalgesic HbSS mice, but not in control (HbAA) mice expressing normal human HbA. JZL184, an inhibitor of 2-AG hydrolysis, also produced hyperalgesia in non-hyperalgesic HbSS or hemizygous (HbAS) mice, but did not influence hyperalgesia in hyperalgesic HbSS mice. Systemic and intraplantar administration of KT109, an inhibitor of DAGLβ, decreased mechanical and heat hyperalgesia in HbSS mice. The decrease in hyperalgesia was accompanied by reductions in 2-AG, PGE2 and PGE2-G in the blood. These results indicate that maintaining the physiological level of 2-AG in the blood by targeting DAGLβ may be a novel and effective approach to treat pain in SCD.
MeSH
Hematology, Anemia, Sickle Cell, Hyperalgesia, Pain, Cells, Therapeutics, Blood, Dinoprostone
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- Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years. Pharmacol Rev, 2023
- Endocannabinoid biosynthetic enzymes regulate pain response via LKB1-AMPK signaling. Proc Natl Acad Sci U S A, 2023
- Mouse models of sickle cell disease: Imperfect and yet very informative. Blood Cells Mol Dis, 2023
- Pain mechanisms in sickle cell disease. Are we closer to a breakthrough? Haematologica, 2023
- Monoacylglycerol Lipase Protects the Presynaptic Cannabinoid 1 Receptor from Desensitization by Endocannabinoids after Persistent Inflammation. J Neurosci, 2023
- Differential roles of diacylglycerol lipase (DAGL) enzymes in nicotine withdrawal. Brain Res, 2023
- Cold exposure induces vaso-occlusion and pain in sickle mice that depend on complement activation. Blood, 2023