title: Mesenchymal Stem Cells Reversed Morphine Tolerance and Opioid-induced Hyperalgesia.
abstract: More than 240 million opioid prescriptions are dispensed annually to treat pain in the US. The use of opioids is commonly associated with opioid tolerance (OT) and opioid-induced hyperalgesia (OIH), which limit efficacy and compromise safety. The dearth of effective way to prevent or treat OT and OIH is a major medical challenge. We hypothesized that mesenchymal stem cells (MSCs) attenuate OT and OIH in rats and mice based on the understanding that MSCs possess remarkable anti-inflammatory properties and that both OT and chronic pain are associated with neuroinflammation in the spinal cord. We found that the development of OT and OIH was effectively prevented by either intravenous or intrathecal MSC transplantation (MSC-TP), which was performed before morphine treatment. Remarkably, established OT and OIH were significantly reversed by either intravenous or intrathecal MSCs when cells were transplanted after repeated morphine injections. The animals did not show any abnormality in vital organs or functions. Immunohistochemistry revealed that the treatments significantly reduced activation level of microglia and astrocytes in the spinal cord. We have thus demonstrated that MSC-TP promises to be a potentially safe and effective way to prevent and reverse two of the major problems of opioid therapy.
authors.affiliation: Departments of Pain Management and Neurosciences, Lerner Research Institute and Anaesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.|Department of Anesthesiology, Beijing Hospital, No. 1 Dahua Road, Beijing 100730, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Hua
authors.affiliation: Departments of Pain Management and Neurosciences, Lerner Research Institute and Anaesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: LiPing
authors.initials: L
authors.lastname: Liu
authors.affiliation: Departments of Pain Management and Neurosciences, Lerner Research Institute and Anaesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Shen
authors.affiliation: Departments of Pain Management and Neurosciences, Lerner Research Institute and Anaesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Departments of Pain Management and Neurosciences, Lerner Research Institute and Anaesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Aijun
authors.initials: A
authors.lastname: Liu
authors.affiliation: Departments of Pain Management and Neurosciences, Lerner Research Institute and Anaesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Departments of Pain Management and Neurosciences, Lerner Research Institute and Anaesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Tingyu
authors.initials: T
authors.lastname: Qu
authors.affiliation: Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: HongNa
authors.initials: H
authors.lastname: Yang
authors.affiliation: Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Departments of Pain Management and Neurosciences, Lerner Research Institute and Anaesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Wu
authors.affiliation: Departments of Pain Management and Neurosciences, Lerner Research Institute and Anaesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: John
authors.initials: J
authors.lastname: Narouze
authors.affiliation: Departments of Pain Management and Neurosciences, Lerner Research Institute and Anaesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Departments of Pain Management and Neurosciences, Lerner Research Institute and Anaesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation; D004361:Drug Tolerance / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced* / Q000628:therapy*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000166:cytology / Q000187:drug effects; D009020:Morphine / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects
chemical_list: C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; C000614142:Gfap protein, rat; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D009020:Morphine