1. Targeting sickle pain with novel therapies and developing methods to quantify pain Kalpna Gupta Vascular Biology Centre Division of Hematology, Oncology and Transplantation Department of Medicine University of Minnesota Medical School Minneapolis, MN Email: gupta014@umn.edu

2. Pain (Nociception) Spinal Activation Phospho- P38/ MAPK ERK TLR4 ↑ IL6 ↑ COX-2 Leg ulcer  Hypoxia, ischemia, reperfusion injury  Vascular/neu ral aberrations  Free heme  Inflammation Pain in Sickle Cell Disease: A complex synergism between peripheral and central mechanisms

3. How do we quantify pain? How do we convey the “pain” as soon as it starts to the healthcare providers? Can diet and alternative therapies help reduce pain? What are the potential novel therapies to treat pain without an inadvertent effect? Recognizing the problem and finding solutions to treat sickle pain

4. Action Units Normal (~22˚C) Cold (4˚C) Eyes are more circular and open Eyes are tightly squeezed, and oval shape Ears erect & perpendicular to the neck line Ears are parallel to the neck line Nose is smooth without skin tightening Tightening of nose with an extension of skin visible Cheek is smooth Convex, similar to “puffing” of cheeks Orbital Tightening Ear Position Cheek Bulge Nose Bulge Cold leads to changes in facial expressions

5. Facial expression readout to quantify pain from remote access? Goal: To develop pain quantification on images transmitted through a cell phone from the patient’s home to the healthcare provider at a distant location. Lucey et al. Int Conf Affect Comput Intell Interact Workshops. 2009:1-8

6. Thakur AS, et al. Hematological Parameters and RBC TBARS Level of CoQ10 Supplemented Tribal Sickle Cell Patients: A Hospital Based Study. Indian J Clin Biochem. 2013 Apr;28(2):185-8 Dose Coenzyme Q10: 15 mg/Kg/day Curcumin: 45 mg/Kg/day Curcumin and CoQ10 reduce pain in sickle mice

7. †, vs HbSS RD/M- *, vs BL High calorie diet and mating attenuate pain in sickle mice. Increase of mechanical hyperalgesia Sickle Control vehicle treatments

8. Potential strategies to improve pain treatment  Cannabinoids?  AT-200 a nociceptin receptor agonist provides analgesia in chronic and hypoxia/reoxygenation induced pain in sickle mice.  Mast cell inhibition with imatinib may reduce pain and improve the sensitivity to opioid-analgesia.  Salubrinal reduces pain and increases HbF expression in human erythroid cells.

9. NHLBI, UO1HL117664; RO1: HL68802; HL103733; HL68802-06S1; HL68802-7S1 Institute for Engineering in Medicine University of Minnesota Foundation Dean’s and Department of Medicine Funds Collaborators Saad Bedros, Engineering Bin He, Engineering Wei Chen, Engineering Univ of MN Resources University Imaging Centre Research Animal Resources Characterization Facility (EM) Cancer Center CTSI MSI Carol Taubert (Illustrations) Lab Members Ying Wang, MD, PhD Huy Tran Jianxun Lei, PhD Jinny A Paul, PhD Lucile Vincent, PhD Yessenia Guevara, PhD Yann Lamarre, PhD Maureen Reidl, PhD Joe Cataldo, PhD Megan Uhelski, PhD Lab Members Julia Nguyen Barbara Benson Ritu Jha Kathryn Luk Susan Thompson Lindsey Skubitz Thu Duong Jonathan Luk Paul Aditya M Mittal Deniz Arcan-Fang ACKNOWLEDGEMENTS