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 #
5U01HL117664-02
Application #
8722605
Study Section
Special Emphasis Panel (ZHL1-CSR-C (F1))
Program Officer
Luksenburg, Harvey
Project Start
2013-08-15
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$1,855,301
Indirect Cost
$504,532
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
Jiaen Liu; Van de Moortele, Pierre-Francois; Xiaotong Zhang et al. (2016) Simultaneous Quantitative Imaging of Electrical Properties and Proton Density From B1 Maps Using MRI. IEEE Trans Med Imaging 35:2064-2073
He, Bin (2016) Focused Ultrasound Help Realize High Spatiotemporal Brain Imaging?-A Concept on Acousto-Electrophysiological Neuroimaging. IEEE Trans Biomed Eng 63:2654-2656
Li, Xu; Yu, Kai; He, Bin (2016) Magnetoacoustic tomography with magnetic induction (MAT-MI) for imaging electrical conductivity of biological tissue: a tutorial review. Phys Med Biol 61:R249-R270
Vincent, Lucile; Vang, Derek; Nguyen, Julia et al. (2016) Cannabinoid receptor-specific mechanisms to alleviate pain in sickle cell anemia via inhibition of mast cell activation and neurogenic inflammation. Haematologica 101:566-77
Wang, Ying; Lei, Jianxun; Gupta, Mihir et al. (2016) Electroacupuncture in conscious free-moving mice reduces pain by ameliorating peripheral and central nociceptive mechanisms. Sci Rep 6:34493
Yu, Kai; Sohrabpour, Abbas; He, Bin (2016) Electrophysiological Source Imaging of Brain Networks Perturbed by Low-intensity Transcranial Focused Ultrasound. IEEE Trans Biomed Eng :
Sohrabpour, Abbas; Ye, Shuai; Worrell, Gregory A et al. (2016) Noninvasive Electromagnetic Source Imaging and Granger Causality Analysis: An Electrophysiological Connectome (eConnectome) Approach. IEEE Trans Biomed Eng 63:2474-2487
Nwankwo, Jennifer O; Lei, Jianxun; Xu, Jian et al. (2016) Genetic inactivation of calpain-1 attenuates pain sensitivity in a humanized mouse model of sickle cell disease. Haematologica 101:e397-e400
Sohrabpour, Abbas; Lu, Yunfeng; Worrell, Gregory et al. (2016) Imaging brain source extent from EEG/MEG by means of an iteratively reweighted edge sparsity minimization (IRES) strategy. Neuroimage 142:27-42
Huishi Zhang, Clara; Sohrabpour, Abbas; Lu, Yunfeng et al. (2016) Spectral and spatial changes of brain rhythmic activity in response to the sustained thermal pain stimulation. Hum Brain Mapp 37:2976-91

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