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Papers of the Week

Papers: 23 Feb 2019 - 1 Mar 2019

Human Studies

2019 May 02




Editor's Pick

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


Khasabova IA, Uhelski M, Khasabov S, Gupta K, Seybold VS, Simone DA
Blood. 2019 May 02; 133(18):1989-1998.
PMID: 30796025.


Pain is a characteristic feature of sickle cell disease (SCD), one 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 (DRGs) and spinal cord in HbSS-BERK mice. In addition to arachidonic acid, COX-2 oxidizes the endocannabinoid 2-arachidonoylglycerol (2-AG) to produce prostaglandin E-glycerol (PGE-G); PGE-G is known to produce hyperalgesia. We tested the hypothesis that PGE-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 -flurbiprofen preferentially reduced production of PGE-G over that of PGE in DRGs, decreased mechanical and thermal hyperalgesia as well as decreased sensitization of nociceptors in HbSS-BERK mice. The same dose of -flurbiprofen had no behavioral effect in HbAA-BERK mice, the transgenic control, but local injection of PGE-G into the hind paw of HbAA-BERK mice produced sensitization of nociceptors and hyperalgesia. Co-administration of a P2Y6 receptor antagonist blocked the effect of PGE-G indicating this receptor is a mediator of pain in SCD. The ability of -flurbiprofen to block the synthesis of PGE-G and to normalize levels of 2-AG suggests that -flurbiprofen may be beneficial to treat pain in SCD, thereby reducing the use of opioids to relieve pain.