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

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

Key Points

  • PGE2-G was elevated in sensory neurons of transgenic mice with SCD. This derivative of 2-AG produced hyperalgesia in control mice.

  • Blocking production of PGE2-G in mice with SCD inhibited hyperalgesia, suggesting a novel approach to treat pain in the disease.

Publisher's Note: There is a Blood Commentary on this article in this issue.


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.

  • Submitted November 2, 2018.
  • Accepted February 12, 2019.
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