Sickle cell disease (SCD) is an inherited hematologic disorder accompanied by severe pain, inflammation and vascular injury. We propose that nociceptor activation by ongoing hypoxia/reperfusion (H/R) injury leads to the release of neuropeptides by sensory nerves in the skin, stimulating vascular insult and mast cell activation in SCD. In turn, mast cell tryptase activates protease activated receptor 2 (PAR 2) on sensory nerve endings maintaining nociceptor sensitization and release of SP and CGRP resulting in exaggerated neuroinflammation, vascular injury and central sensitization in SCD. Sickle mice show hyperalgesia, which is further elevated by H/R and attenuated by non-selective cannabinoid receptor agonist CP55940. Our preliminary data indicate that mast cell activity and Evans blue dye leakage are increased in the skin of sickle mice Vs control, which are inhibited by CP55940. Our general hypothesis is that neurogenic inflammation contributes to pain in SCD and that cannabinoids offer the unique advantage of providing analgesia by disrupting neurogenic inflammation and nociceptor sensitization, thereby preventing central sensitization. We also hypothesize that objective, non- invasive measures of pain - EEG and functional MRI - can be used to optimize analgesic treatments in SCD. These hypotheses will be tested in the following aims. SA#1. A multicellular repertoire involving mast-, endothelial-, glial and neuronal cells orchestrates neurogenic inflammation and hyperalgesia via distinct cellular receptors and signaling pathways, which will be intercepted by cannabinoids utilizing specific cannabinoid receptors (CBR). SA#2. Cannabinoids will attenuate central sensitization in sickle mice and pain in human subjects. SA#3. Simultaneous non-invasive fMRI/EEG multimodal neuroimaging will provides an effective means to quantify pain. We propose to use transgenic sickle mice, and individual cells involved in evoking pain, to perform this translational study. A proof of principle study in humans will be undertaken to examine the effect of Cannabis ion pain in sickle patients. We expect that the multidisciplinary approach combining biochemistry, neurophysiology, pharmacology, behavior and biomedical engineering will advance the treatment of pain in SCD.

Public Health Relevance

Opioids are the only therapy for severe pain in sickle cell disease (SCD), but are often associated with side effects and their use is subject to addiction. Since individuals with SCD suffer with pain throughout life, it is critical to develop novel methods to quantify pain so that pain can be treated effectively. We propose to examine the mechanism(s) that cause ongoing pain and if Cannabis-based drugs can provide analgesia to treat pain in SCD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01HL117664-05S2
Application #
9771125
Study Section
Program Officer
Luksenburg, Harvey
Project Start
2018-09-15
Project End
2019-05-31
Budget Start
2018-09-15
Budget End
2019-05-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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