title: Bone marrow stromal cells produce long-term pain relief in rat models of persistent pain.
abstract: Chronic pain conditions are difficult to treat and are major health problems. Bone marrow stromal cells (BMSCs) have generated considerable interest as a candidate for cell-based therapy. BMSCs are readily accessible and are easy to isolate and expand ex vivo. Clinical studies show that direct injection of BMSCs does not produce unwanted side effects and is well tolerated and safe. Here, we show that a single systemic (intravenous) or local injection (into the lesion site) of rat primary BMSCs reversed pain hypersensitivity in rats after injury and that the effect lasted until the conclusion of the study at 22 weeks. The pain hypersensitivity was rekindled by naloxone hydrochloride, an opioid receptor antagonist that acts peripherally and centrally, when tested at 1-5 weeks after BMSC infusion. In contrast, naloxone methiodide, a peripherally acting opioid receptor antagonist, only rekindled hyperalgesia in the first 3 weeks of BMSC treatment. Focal downregulation of brainstem mu opioid receptors by RNA interference (RNAi) reversed the effect of BMSCs, when RNAi was introduced at 5- but not 1-week after BMSC transplantation. Thus, BMSCs produced long-term relief of pain and this effect involved activation of peripheral and central opioid receptors in distinct time domains. The findings prompt studies to elucidate the cellular mechanisms of the BMSC-induced pain relieving effect and translate these observations into clinical settings.
authors.affiliation: Department of Neural and Pain Sciences, Dental School, University of Maryland, Baltimore, Maryland 21201-1586, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Hu
authors.initials: H
authors.lastname: Wang
authors.forename: Shiping
authors.initials: S
authors.lastname: Zou
authors.forename: Ming
authors.initials: M
authors.lastname: Gu
authors.forename: Mineo
authors.initials: M
authors.lastname: Watanabe
authors.forename: Feng
authors.initials: F
authors.lastname: Wei
authors.forename: Ronald
authors.initials: R
authors.lastname: Dubner
authors.forename: George T-J
authors.initials: GT
authors.lastname: Huang
authors.forename: Ke
authors.initials: K
authors.lastname: Ren
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D048430:Cell Shape; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D054024:Myelencephalon / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D059408:Pain Management; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000637:transplantation*; D013708:Tendon Injuries / Q000628:therapy
chemical_list: D015703:Antigens, CD; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009270:Naloxone