Non-healing, painful leg ulcers present a major therapeutic challenge in sickle cell disease. We observed that topical application of opioids stimulates angiogenesis and accelerates healing of ischemic wounds in rats. We hypothesize that specific opioid receptor(s) in the wound modulate angiogenesis and healing through distinct cellular and molecular mechanism(s). Thus topically applied opioids might promote healing of chronic painful ulcers in sickle cell disease. We will test this via:
Aim # 1: Opioid receptor(s) stimulate pro-proliferative signaling by, [a] transactivating VEGF receptor-2 on endothelial cells, [b] stimulating MAPK/ERK and STAT3 signaling pathway and [c] by mediating the effect of endogenous opioids produced by keratinocytes.
AIM # 2: Opioid(s)/opioid receptor(s) in the skin are essential for maintenance of normal skin architecture and are involved in wound healing. We will examine the: [a] alterations in wound healing in opioid receptor(s)/ligand knockout mice to identify the specific opioid receptor(s) involved in wound healing, [b] cell specific opioid receptor(s)/endogenous opioid expression in the wild type vs sickle mouse skin.
AIM #3 : Topically applied opioids in clinically relevant doses promote: [a] wound healing in sickle mice and [b] analgesia to wound associated nociception.
AIM # 4: Stressed and ischemic sickle milieu induced perturbation of the interdependent triad of angiogenesis, lymphangiogenesis and neurogenesis underlies the pathogenesis of non-healing wounds in SCD. We will use an open ischemic wound model that mimics human ischemic skin ulcers. In vivo studies will be performed on transgenic mice expressing sickle hemoglobin mimicking human disease and mice deleted for opioid receptor(s) or ligands, while in vitro experiments will use human dermal microvascular endothelial cells or blood outgrowth endothelial cells from different mice, and keratinocytes. If our hypotheses are true, this project may lead to the development of an effective treatment for painful leg ulcers in sickle cell disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068802-07
Application #
7858330
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Luksenburg, Harvey
Project Start
2002-04-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
7
Fiscal Year
2010
Total Cost
$413,000
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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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
Gupta, Mihir; Poonawala, Tasneem; Farooqui, Mariya et al. (2015) Topical fentanyl stimulates healing of ischemic wounds in diabetic rats. J Diabetes 7:573-583
Vang, Derek; Paul, Jinny A; Nguyen, Julia et al. (2015) Small-molecule nociceptin receptor agonist ameliorates mast cell activation and pain in sickle mice. Haematologica 100:1517-25
Gupta, Mihir; Msambichaka, Lilian; Ballas, Samir K et al. (2015) Morphine for the treatment of pain in sickle cell disease. ScientificWorldJournal 2015:540154
Nguyen, J; Luk, K; Vang, D et al. (2014) Morphine stimulates cancer progression and mast cell activation and impairs survival in transgenic mice with breast cancer. Br J Anaesth 113 Suppl 1:i4-13
Zylla, D; Kuskowski, M A; Gupta, K et al. (2014) Association of opioid requirement and cancer pain with survival in advanced non-small cell lung cancer. Br J Anaesth 113:i109-i116
Dandapat, Abhijit; Bosnakovski, Darko; Hartweck, Lynn M et al. (2014) Dominant lethal pathologies in male mice engineered to contain an X-linked DUX4 transgene. Cell Rep 8:1484-96
Vincent, Lucile; Vang, Derek; Nguyen, Julia et al. (2013) Mast cell activation contributes to sickle cell pathobiology and pain in mice. Blood 122:1853-62

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