Sickle cell disease (SCD) SCD is an autosomal recessive disorder characterized by hemolytic anemia and systemic inflammation that afflicts millions of people worldwide. Chronic pain is a hallmark of SCD. Intense ongoing pain and episodic pain starts early in life and increase in severity with age. The primary treatment for pai is opioids which have a variety of undesirable side effects such as respiratory depression and tolerance, and may contribute to organ damage. Although the pathophysiology of SCD is well understood, little is known about the mechanisms that mediate the pain in SCD. We will use an established mouse model of SCD, Berkley (BERK) mice, to study peripheral mechanisms of pain in SCD. These mice offer a unique advantage because of their similarity to human genetic, hematologic and pathological disease, including ongoing pain and hyperalgesia. Earlier studies and preliminary data show that these mice exhibit increased levels of cyclooxygenase (COX)-2 in the spinal cord and dorsal root ganglia (DRG) and a decrease in tissue content of 2-arachidonoyl-sn-glycerol (2-AG). COX-2 may contribute to pain through the formation of prostaglandins as well as prostaglandin-glycerol esters (PG-Gs) generated from the oxidation of 2-AG by COX-2 (e.g., PGE2-G) that sensitize nociceptors. Our general hypothesis is that PGE2-G contributes to pain in SCD. A multidisciplinary approach incorporating parallel biochemical, behavioral, cellular and electrophysiological studies in mice with SCD will test this hypothesis. We will determine whether PGE2-G is elevated in DRG and peripheral tissue in sickle mice (Aim 1), whether deceased production of PGE2-G decreases hyperalgesia (Aim 2), and whether PGE2-G sensitizes nociceptors in control mice and contributes to nociceptor sensitization in sickle mice (Aim 3). These studies will provide new insights into the peripheral mechanisms underlying pain in SCD, as well as new information on the role of PGE2-G in nociceptor sensitization, and may help identify new approaches for treating the chronic, debilitating pain in SCD.

Public Health Relevance

Severe, chronic pain that is difficult to treat accompanies sickle cell disease (SCD). We will use a transgenic mouse model of SCD to study peripheral mechanisms of pain in this disease. Our results may identify novel approaches for treating the debilitating pain associated with SCD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL135895-17
Application #
9343042
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Luksenburg, Harvey
Project Start
2000-02-03
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
17
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Cataldo, Giuseppe; Lunzer, Mary M; Olson, Julie K et al. (2018) Bivalent ligand MCC22 potently attenuates nociception in a murine model of sickle cell disease. Pain 159:1382-1391
Uhelski, Megan L; Gupta, Kalpna; Simone, Donald A (2017) Sensitization of C-fiber nociceptors in mice with sickle cell disease is decreased by local inhibition of anandamide hydrolysis. Pain 158:1711-1722