title: CXCL10 controls inflammatory pain via opioid peptide-containing macrophages in electroacupuncture.
abstract: Acupuncture is widely used for pain treatment in patients with osteoarthritis or low back pain, but molecular mechanisms remain largely enigmatic. In the early phase of inflammation neutrophilic chemokines direct opioid-containing neutrophils in the inflamed tissue and stimulate opioid peptide release and antinociception. In this study the molecular pathway and neuroimmune connections in complete Freund's adjuvant (CFA)-induced hind paw inflammation and electroacupuncture for peripheral pain control were analyzed. Free moving Wistar rats with hind paw inflammation were treated twice with electroacupuncture at GB30 (Huan Tiao--gall bladder meridian) (day 0 and 1) and analyzed for mechanical and thermal nociceptive thresholds. The cytokine profiles as well as the expression of opioid peptides were quantified in the inflamed paw. Electroacupuncture elicited long-term antinociception blocked by local injection of anti-opioid peptide antibodies (beta-endorphin, met-enkephalin, dynorphin A). The treatment altered the cytokine profile towards an anti-inflammatory pattern but augmented interferon (IFN)-gamma and the chemokine CXCL10 (IP-10: interferon gamma-inducible protein) protein and mRNA expression with concomitant increased numbers of opioid peptide-containing CXCR3+ macrophages. In rats with CFA hind paw inflammation without acupuncture repeated injection of CXCL10 triggered opioid-mediated antinociception and increase opioid-containing macrophages. Conversely, neutralization of CXCL10 time-dependently decreased electroacupuncture-induced antinociception and the number of infiltrating opioid peptide-expressing CXCR3+ macrophages. In summary, we describe a novel function of the chemokine CXCL10--as a regulator for an increase of opioid-containing macrophages and antinociceptive mediator in inflammatory pain and as a key chemokine regulated by electroacupuncture.
authors.affiliation: Department of Anesthesiology, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Rebekka
authors.initials: R
authors.lastname: Gehringer
authors.affiliation: Department of Anesthesiology and Critical Care, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Shaaban A
authors.initials: SA
authors.lastname: Mousa
authors.affiliation: Department of Anesthesiology, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Hackel
authors.affiliation: Department of Anesthesiology, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Brack
authors.affiliation: Department of Anesthesiology, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Heike L
authors.initials: HL
authors.lastname: Rittner
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D054357:Chemokine CXCL10 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D015671:Electroacupuncture / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay; D007249:Inflammation / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D059225:Nociception; D018847:Opioid Peptides / Q000737:chemistry*; D059408:Pain Management; D010147:Pain Measurement; D017288:Pain Threshold; D051381:Rats; D017208:Rats, Wistar; D054367:Receptors, CXCR3 / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D054357:Chemokine CXCL10; C091326:Cxcl10 protein, rat; C515189:Cxcr3 protein, rat; D016207:Cytokines; D018847:Opioid Peptides; D054367:Receptors, CXCR3; D007371:Interferon-gamma
references.citation: J Neuroimmunol. 2004 Jun;151(1-2):40-4
references.pmid: 15145602
references.citation: Pain. 2012 Aug;153(8):1720-1726
references.pmid: 22727499
references.citation: Anesth Analg. 2009 Nov;109(5):1666-73
references.pmid: 19843806
references.citation: Brain Res. 2004 Sep 10;1020(1-2):18-29
references.pmid: 15312783
references.citation: J Immunol. 2011 Jun 1;186(11):6417-26
references.pmid: 21515789
references.citation: Ann Intern Med. 2005 Apr 19;142(8):651-63
references.pmid: 15838072
references.citation: Anesthesiology. 2001 Aug;95(2):500-8
references.pmid: 11506126
references.citation: Brain Res. 2011 Jun 13;1395:38-45
references.pmid: 21565329
references.citation: FASEB J. 2006 Dec;20(14):2627-9
references.pmid: 17060402
references.citation: Brain Res Bull. 2004 Mar 15;63(2):99-103
references.pmid: 15130698
references.citation: J Exp Med. 2010 Aug 30;207(9):1951-66
references.pmid: 20733031
references.citation: Nat Neurosci. 2010 Jul;13(7):883-8
references.pmid: 20512135
references.citation: Brain Res. 2005 Jun 28;1048(1-2):235-40
references.pmid: 15922310
references.citation: Pain. 2004 Dec;112(3):229-238
references.pmid: 15561377
references.citation: J Leukoc Biol. 2005 Dec;78(6):1210-4
references.pmid: 16204635
references.citation: J Leukoc Biol. 2006 May;79(5):1022-32
references.pmid: 16522746
references.citation: Pain. 2012 Sep;153(9):1883-1889
references.pmid: 22770838
references.citation: Zhen Ci Yan Jiu. 2011 Apr;36(2):79-84
references.pmid: 21717772
references.citation: Biochemistry. 2002 Aug 20;41(33):10418-25
references.pmid: 12173928
references.citation: Pain. 2004 Mar;108(1-2):67-75
references.pmid: 15109509
references.citation: Cytokine. 2010 Jun;50(3):335-40
references.pmid: 20231101
references.citation: PLoS Pathog. 2009 Apr;5(4):e1000362
references.pmid: 19343210
references.citation: Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20602-7
references.pmid: 23185004
references.citation: Pain. 1983 Jun;16(2):109-110
references.pmid: 6877845
references.citation: Nat Med. 2003 Nov;9(11):1353-4
references.pmid: 14595426
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14092-7
references.pmid: 16174730
references.citation: J Pain. 2013 Sep;14(9):897-910
references.pmid: 23683582
references.citation: PLoS One. 2013 May 02;8(5):e63564
references.pmid: 23658840
references.citation: J Immunol. 2013 May 15;190(10):4929-36
references.pmid: 23585676
references.citation: FASEB J. 2012 Dec;26(12):5161-71
references.pmid: 22923332
references.citation: Eur J Pain. 2012 May;16(5):624-35
references.pmid: 22337285
references.citation: Anesthesiology. 2004 Jan;100(1):149-57
references.pmid: 14695736
references.citation: Mol Pain. 2011 Dec 19;7:98
references.pmid: 22177137
references.citation: Neurosci Lett. 2004 May 6;361(1-3):258-61
references.pmid: 15135942
references.citation: Proc Natl Acad Sci U S A. 1994 May 10;91(10):4219-23
references.pmid: 7910403
references.citation: J Leukoc Biol. 2008 Nov;84(5):1264-70
references.pmid: 18703681
references.citation: Brain Res. 2010 Oct 8;1355:97-103
references.pmid: 20707990
references.citation: Can J Physiol Pharmacol. 2012 Apr;90(4):395-405
references.pmid: 22443108
references.citation: Eur J Pharmacol. 1993 Oct 5;242(3):229-35
references.pmid: 8281987
references.citation: Explore (NY). 2005 Sep;1(5):365-71
references.pmid: 16781567
references.citation: J Neuroimmune Pharmacol. 2010 Dec;5(4):489-95
references.pmid: 20354805
references.citation: Eur J Pain. 2013 Nov;17(10):1447-57
references.pmid: 23649949
references.citation: PLoS One. 2011;6(8):e24290
references.pmid: 21904626
references.citation: Lancet. 1980 Nov 1;2(8201):946-9
references.pmid: 6107591
references.citation: Nature. 1980 Jan 17;283(5744):243-4
references.pmid: 6243393
references.citation: J Exp Med. 1993 Jun 1;177(6):1809-14
references.pmid: 8496693
references.citation: Brain Res. 2004 Sep 10;1020(1-2):12-7
references.pmid: 15312782
references.citation: Blood. 2003 May 15;101(10):3985-90
references.pmid: 12446452
references.citation: BMC Complement Altern Med. 2013 Jan 28;13:22
references.pmid: 23356671