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 - EEC 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 provide 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 principl 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
4U01HL117664-04
Application #
9095447
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Luksenburg, Harvey
Project Start
2013-08-15
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
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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Vijayakumar, Vishal; Case, Michelle; Shirinpour, Sina et al. (2017) Quantifying and Characterizing Tonic Thermal Pain Across Subjects From EEG Data Using Random Forest Models. IEEE Trans Biomed Eng 64:2988-2996
Guo, Zhijun; Sevrioukova, Irina F; Denisov, Ilia G et al. (2017) Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria. Cell Chem Biol 24:1259-1275.e6
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Wang, Ying; Gupta, Mihir; Poonawala, Tasneem et al. (2017) Opioids and opioid receptors orchestrate wound repair. Transl Res 185:13-23
Tran, Huy; Gupta, Mihir; Gupta, Kalpna (2017) Targeting novel mechanisms of pain in sickle cell disease. Hematology Am Soc Hematol Educ Program 2017:546-555
Case, Michelle; Zhang, Huishi; Mundahl, John et al. (2017) Characterization of functional brain activity and connectivity using EEG and fMRI in patients with sickle cell disease. Neuroimage Clin 14:1-17

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