PMID- 30459569 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20201001 IS - 1662-5145 (Print) IS - 1662-5145 (Electronic) IS - 1662-5145 (Linking) VI - 12 DP - 2018 TI - NF-KappaB Pathway Is Involved in Bone Marrow Stromal Cell-Produced Pain Relief. PG - 49 LID - 10.3389/fnint.2018.00049 [doi] LID - 49 AB - Bone marrow stromal cells (BMSCs) produce long-lasting attenuation of pain hypersensitivity. This effect involves BMSC's ability to interact with the immune system and activation of the endogenous opioid receptors in the pain modulatory circuitry. The nuclear factor kappa B (NF-kappaB) protein complex is a key transcription factor that regulates gene expression involved in immunity. We tested the hypothesis that the NF-kappaB signaling plays a role in BMSC-induced pain relief. We focused on the rostral ventromedial medulla (RVM), a key structure in the descending pain modulatory pathway, that has been shown to play an important role in BMSC-produced antihyperalgesia. In Sprague-Dawley rats with a ligation injury of the masseter muscle tendon (TL), BMSCs (1.5 M/rat) from donor rats were infused i.v. at 1 week post-TL. P65 exhibited predominant neuronal localization in the RVM with scattered distribution in glial cells. At 1 week, but not 8 weeks after BMSC infusion, western blot and immunostaining showed that p65 of NF-kappaB was significantly increased in the RVM. Given that chemokine signaling is critical to BMSCs' pain-relieving effect, we further evaluated a role of chemokine signaling in p65 upregulation. Prior to infusion of BMSCs, we transduced BMSCs with Ccl4 shRNA, incubated BMSCs with RS 102895, a CCR2b antagonist, or maraviroc, a CCR5 antagonist. The antagonism of chemokines significantly reduced BMSC-induced upregulation of p65, suggesting that upregulation of p65 was related to BMSCs' pain-relieving effect. We then tested the effect of a selective NF-kappaB activation inhibitor, BAY 11-7082. The mechanical hyperalgesia of the rat was assessed with the von Frey method. In the pre-treatment experiment, BAY 11-7082 (2.5 and 25 pmol) was injected into the RVM at 2 h prior to BMSC infusion. Pretreatment with BAY 11-7082 attenuated BMSCs' antihyperalgesia, but post-treatment at 5 weeks post-BMSC was not effective. On the contrary, in TL rats receiving BAY 11-7082 without BMSCs, TL-induced hyperalgesia was attenuated, consistent with dual roles of NF-kappaB in pain hypersensitivity and BMSC-produced pain relief. These results indicate that the NF-kappaB signaling pathway in the descending circuitry is involved in initiation of BMSC-produced behavioral antihyperalgesia. FAU - Guo, Wei AU - Guo W AD - Department of Neural and Pain Sciences, School of Dentistry & Program in Neuroscience, University of Maryland, Baltimore, MD, United States. FAU - Imai, Satoshi AU - Imai S AD - Department of Neural and Pain Sciences, School of Dentistry & Program in Neuroscience, University of Maryland, Baltimore, MD, United States. AD - Department of Clinical Pharmacology & Therapeutics, Kyoto University Hospital, Kyoto, Japan. FAU - Yang, Jia-Le AU - Yang JL AD - Department of Neural and Pain Sciences, School of Dentistry & Program in Neuroscience, University of Maryland, Baltimore, MD, United States. FAU - Zou, Shiping AU - Zou S AD - Department of Neural and Pain Sciences, School of Dentistry & Program in Neuroscience, University of Maryland, Baltimore, MD, United States. FAU - Li, Huijuan AU - Li H AD - Department of Neural and Pain Sciences, School of Dentistry & Program in Neuroscience, University of Maryland, Baltimore, MD, United States. AD - Department of Neurology, The 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. FAU - Xu, Huakun AU - Xu H AD - Department of Advanced Oral Sciences and Therapeutics, University of Maryland School of Dentistry, Baltimore, MD, United States. FAU - Moudgil, Kamal D AU - Moudgil KD AD - Department of Microbiology & Immunology, University of Maryland, Baltimore, MD, United States. FAU - Dubner, Ronald AU - Dubner R AD - Department of Neural and Pain Sciences, School of Dentistry & Program in Neuroscience, University of Maryland, Baltimore, MD, United States. FAU - Wei, Feng AU - Wei F AD - Department of Neural and Pain Sciences, School of Dentistry & Program in Neuroscience, University of Maryland, Baltimore, MD, United States. FAU - Ren, Ke AU - Ren K AD - Department of Neural and Pain Sciences, School of Dentistry & Program in Neuroscience, University of Maryland, Baltimore, MD, United States. LA - eng GR - R01 DE021804/DE/NIDCR NIH HHS/United States GR - R01 DE025137/DE/NIDCR NIH HHS/United States GR - R01 NS091296/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20181016 PL - Switzerland TA - Front Integr Neurosci JT - Frontiers in integrative neuroscience JID - 101477950 PMC - PMC6232783 OTO - NOTNLM OT - BAY 11-7082 OT - chemokine OT - mesenchymal stromal cells OT - orofacial pain OT - rostral ventromedial medulla OT - tendon ligation EDAT- 2018/11/22 06:00 MHDA- 2018/11/22 06:01 PMCR- 2018/01/01 CRDT- 2018/11/22 06:00 PHST- 2018/08/03 00:00 [received] PHST- 2018/09/26 00:00 [accepted] PHST- 2018/11/22 06:00 [entrez] PHST- 2018/11/22 06:00 [pubmed] PHST- 2018/11/22 06:01 [medline] PHST- 2018/01/01 00:00 [pmc-release] AID - 10.3389/fnint.2018.00049 [doi] PST - epublish SO - Front Integr Neurosci. 2018 Oct 16;12:49. doi: 10.3389/fnint.2018.00049. eCollection 2018.