91桃色

Abstract

Mast cells are tissue resident granulocytes known for their role in itch and anaphylaxis. We examined the contribution of mast cell activation in chronic and acute pain. We used homozygous BERK sickle mice that have constitutive chronic pain and hypoxia/re-oxygenation evoked acute pain. These mice mimic the features of clinical sickle cell disease (SCD), which is accompanied by severe chronic pain and recurrent episodes of acute pain. We found that mast cell degranulation/activation is significantly higher in the skin of sickle mice as compared to controls. This increased mast cell activation contributes to promoting neurogenic inflammation and nociceptor activation via the release of tryptase and substance P in the skin and dorsal root ganglion. Inhibition of mast cells with imatinib in vivo, led to a significant decrease in the release of cytokines from skin biopsies ex-vivo. Importantly, it led to a correlative decrease between GMCSF and white blood cell counts in sickle mice. Mast cell deletion in sickle mice as well as pharmacologic treatment with imatinib led to a decrease in tonic and hypoxia/reoxygenation evoked acute hyperalgesia in sickle mice. Mast cell stabilizer cromolyn sodium reduced chronic hyperalgesia and improved the outcome of relatively lower dose of morphine, which is otherwise ineffective. We conclude that mast cells provide a druggable target to ameliorate sickle pathophysiology and pain.

Biography

Email: gupta014@umn.edu