Sensitization of nociceptors by prostaglandin E2-glycerol contributes to hyperalgesia in mice with sickle cell disease

Iryna Khasabova, Megan Uhelski, Sergey Khasabov, Kalpna Gupta, Virginia S. Seybold, Donald A Simone

Research output: Contribution to journalArticle

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Abstract

Pain is a characteristic feature of sickle cell disease (SCD), 1 of the most common inherited diseases. Patients may experience acute painful crises as well as chronic pain. In the Berkley transgenic murine model of SCD, HbSS-BERK mice express only human hemoglobin S. These mice share many features of SCD patients, including persistent inflammation and hyperalgesia. Cyclooxygenase-2 (COX-2) is elevated in skin, dorsal root ganglia (DRG), and spinal cord in HbSS-BERK mice. In addition to arachidonic acid, COX-2 oxidizes the endocannabinoid 2-arachidonoylglycerol (2-AG) to produce prostaglandin E2 (PGE2)-glycerol (PGE2-G); PGE2-G is known to produce hyperalgesia. We tested the hypotheses that PGE2-G is increased in DRGs of HbSS-BERK mice and sensitizes nociceptors (sensory neurons that respond to noxious stimuli), and that blocking its synthesis would decrease hyperalgesia in HbSS-BERK mice. Systemic administration of R-flurbiprofen preferentially reduced production of PGE2-G over that of PGE2 in DRGs, decreased mechanical and thermal hyperalgesia, and decreased sensitization of nociceptors in HbSS-BERK mice. The same dose of R-flurbiprofen had no behavioral effect in HbAA-BERK mice (the transgenic control), but local injection of PGE2-G into the hind paw of HbAA-BERK mice produced sensitization of nociceptors and hyperalgesia. Coadministration of a P2Y6 receptor antagonist blocked the effect of PGE2-G, indicating that this receptor is a mediator of pain in SCD. The ability of R-flurbiprofen to block the synthesis of PGE2-G and to normalize levels of 2-AG suggests that R-flurbiprofen may be beneficial to treat pain in SCD, thereby reducing the use of opioids to relieve pain.

Original languageEnglish (US)
Pages (from-to)1989-1998
Number of pages10
JournalBlood
Volume133
Issue number18
DOIs
StatePublished - May 2 2019

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Prostaglandins G
Nociceptors
Hyperalgesia
Sickle Cell Anemia
Dinoprostone
Glycerol
Flurbiprofen
Pain
Diagnosis-Related Groups
Cyclooxygenase 2
Sickle Hemoglobin
Endocannabinoids
Aptitude
Spinal Ganglia
Sensory Receptor Cells
Prostaglandin-Endoperoxide Synthases
Chronic Pain
Opioid Analgesics
Transgenic Mice
Neurons

PubMed: MeSH publication types

  • Journal Article

Cite this

Sensitization of nociceptors by prostaglandin E2-glycerol contributes to hyperalgesia in mice with sickle cell disease. / Khasabova, Iryna; Uhelski, Megan; Khasabov, Sergey; Gupta, Kalpna; Seybold, Virginia S.; Simone, Donald A.

In: Blood, Vol. 133, No. 18, 02.05.2019, p. 1989-1998.

Research output: Contribution to journalArticle

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abstract = "Pain is a characteristic feature of sickle cell disease (SCD), 1 of the most common inherited diseases. Patients may experience acute painful crises as well as chronic pain. In the Berkley transgenic murine model of SCD, HbSS-BERK mice express only human hemoglobin S. These mice share many features of SCD patients, including persistent inflammation and hyperalgesia. Cyclooxygenase-2 (COX-2) is elevated in skin, dorsal root ganglia (DRG), and spinal cord in HbSS-BERK mice. In addition to arachidonic acid, COX-2 oxidizes the endocannabinoid 2-arachidonoylglycerol (2-AG) to produce prostaglandin E2 (PGE2)-glycerol (PGE2-G); PGE2-G is known to produce hyperalgesia. We tested the hypotheses that PGE2-G is increased in DRGs of HbSS-BERK mice and sensitizes nociceptors (sensory neurons that respond to noxious stimuli), and that blocking its synthesis would decrease hyperalgesia in HbSS-BERK mice. Systemic administration of R-flurbiprofen preferentially reduced production of PGE2-G over that of PGE2 in DRGs, decreased mechanical and thermal hyperalgesia, and decreased sensitization of nociceptors in HbSS-BERK mice. The same dose of R-flurbiprofen had no behavioral effect in HbAA-BERK mice (the transgenic control), but local injection of PGE2-G into the hind paw of HbAA-BERK mice produced sensitization of nociceptors and hyperalgesia. Coadministration of a P2Y6 receptor antagonist blocked the effect of PGE2-G, indicating that this receptor is a mediator of pain in SCD. The ability of R-flurbiprofen to block the synthesis of PGE2-G and to normalize levels of 2-AG suggests that R-flurbiprofen may be beneficial to treat pain in SCD, thereby reducing the use of opioids to relieve pain.",
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