title: Further observations on the behavioral and neural effects of bone marrow stromal cells in rodent pain models.
abstract: BACKGROUND
  Bone marrow stromal cells (BMSCs) have shown potential to treat chronic pain, although much still needs to be learned about their efficacy and mechanisms of action under different pain conditions. Here, we provide further convergent evidence on the effects of BMSCs in rodent pain models.
  
  
  RESULTS
  In an orofacial pain model involving injury of a tendon of the masseter muscle, BMSCs attenuated behavioral pain conditions assessed by von Frey filaments and a conditioned place avoidance test in female Sprague-Dawley rats. The antihyperalgesia of BMSCs in females lasted for <8 weeks, which is shorter than that seen in males. To relate preclinical findings to human clinical conditions, we used human BMSCs. Human BMSCs (1.5 M cells, i.v.) attenuated mechanical and thermal hyperalgesia induced by spinal nerve ligation and suppressed spinal nerve ligation-induced aversive behavior, and the effect persisted through the 8-week observation period. In a trigeminal slice preparation, BMSC-treated and nerve-injured C57B/L mice showed reduced amplitude and frequency of spontaneous excitatory postsynaptic currents, as well as excitatory synaptic currents evoked by electrical stimulation of the trigeminal nerve root, suggesting inhibition of trigeminal neuronal hyperexcitability and primary afferent input by BMSCs. Finally, we observed that GluN2A (N-methyl-D-aspartate receptor subunit 2A) tyrosine phosphorylation and protein kinase Cgamma (PKCg) immunoreactivity in rostral ventromedial medulla was suppressed at 8 weeks after BMSC in tendon-injured rats.
  
  
  CONCLUSIONS
  Collectively, the present work adds convergent evidence supporting the use of BMSCs in pain control. As PKCg activity related to N-methyl-D-aspartate receptor activation is critical in opioid tolerance, these results help to understand the mechanisms of BMSC-produced long-term antihyperalgesia, which requires opioid receptors in rostral ventromedial medulla and apparently lacks the development of tolerance.
authors.affiliation: University of Maryland School of Denstistry.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: University of Maryland School of DenstistryUniversity of Maryland School of DentistryUniversity of Maryland School of DentristryUniversity of Maryland School of DentistryUniversity of Maryland School of Dentistry.
authors.forename: Yu-Xia
authors.initials: YX
authors.lastname: Chu
authors.affiliation: University of Maryland School of DenstistryUniversity of Maryland School of DentistryUniversity of Maryland School of DentristryUniversity of Maryland School of DentistryUniversity of Maryland School of Dentistry.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Imai
authors.affiliation: University of Maryland School of Dentistry.
authors.forename: Jia-Le
authors.initials: JL
authors.lastname: Yang
authors.affiliation: University of Maryland School of Dentristry.
authors.forename: Shiping
authors.initials: S
authors.lastname: Zou
authors.affiliation: University of Maryland School of Dentistry.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Mohammad
authors.affiliation: University of Maryland School of DenstistryUniversity of Maryland School of DentistryUniversity of Maryland School of DentristryUniversity of Maryland School of DentistryUniversity of Maryland School of Dentistry.
authors.forename: Feng
authors.initials: F
authors.lastname: Wei
authors.affiliation: University of Maryland School of Dentistry.
authors.forename: Ronald
authors.initials: R
authors.lastname: Dubner
authors.affiliation: University of Maryland School of DenstistryUniversity of Maryland School of DentistryUniversity of Maryland School of DentristryUniversity of Maryland School of DentistryUniversity of Maryland School of Dentistry kren@umaryland.edu.
authors.forename: Ke
authors.initials: K
authors.lastname: Ren
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009270:Naloxone / Q000494:pharmacology; D009437:Neuralgia / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000473:pathology; D013710:Tendons / Q000187:drug effects / Q000473:pathology; D014276:Trigeminal Nerve / Q000187:drug effects / Q000473:pathology
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D009270:Naloxone; C087857:protein kinase C gamma; D011493:Protein Kinase C