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DFG Research Unit FOR 721/2 Molecular Structure and Function of the Tight Junction |
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Project 8 |
Heike Rittner, MD
Dept. of Anesthesia and Critical Care, University Wuerzburg
Alexander Brack, MD
Dept. of Anesthesia and Critical Care, University Wuerzburg
Michael Fromm, Prof. MD
Institute of Clinical Physiology,
Campus Benjamin Franklin,
Charité, Freie Universitaet and Humboldt-Universitaet, Berlin
Tight junction proteins as permeability regulators in the perineurium and the antinociception of perineurally applied pharmaceuticals
Perineurally injected local anesthetics are used for treatment of intra- and postoperative pain. However, they cause unwanted motor blockade and may cause seizures or cardiac arrest after accidental intravascular injection. As an alternative, selective sodium channel blockers or opioids could be used, since they preferentially block pain or sensory senior (= nociceptive) fibers. They are, however, not used because of their low therapeutic index and lack of efficacy. The barrier function perineurium surrounding the nerve could be intentionally impaired by perineural injection of hypertonic saline solution which then could improve the effectiveness and/or therapeutic index of pain relieving drugs.
We examine the pain relieving (= antinociceptive) effect of blockers of voltage-gated sodium channels or opioids, the expression pattern of tight junction proteins in the perineurium of the sciatic nerve, and the mechanism of action of metalloproteinases on the permeability of the perineurium as well as on the expression of tight junction proteins.
Granted by project 8
Dr. Dagmar Hackel
Hackel D, Brack A, Fromm M, Rittner H (2012) Modulation of tight junction proteins in the perineurium for regional pain control. Ann. N.Y. Acad. Sci. 1257: 199-206 (IF 3.2) [PubMed] [WebPage] [PDF] (Review)
Hackel D, Krug SM, Sauer RS, Mousa SA, Böcker A, Pflücke D, Wrede EJ, Kistner K, Hoffmann T, Niedermirtl B, Sommer C, Bloch L, Huber O, Blasig IE, Amasheh S, Reeh PW, Fromm M, Brack A, Rittner HL (2012) Transient opening of the perineurial barrier for analgesic drug delivery. Proc. Natl. Acad. Sci. USA 109(29): E2018-E2027 (IF 9.7) [PubMed] [WebPage] [PDF] TP8+TP1+TP3+TP5
Zwanziger D, Hackel D, Staat C, Böcker A, Brack A, Beyermann M, Rittner HL, Blasig IE (2012) A peptidomimetic tight junction modulator to improve regional analgesia. Mol. Pharmaceut. 9(6): 1785-1794 (IF 5.4) [PubMed] [WebPage] [PDF]]
Rittner HL, Amasheh S, Moshourab R, Hackel D, Yamdeu RS, Fromm M, Stein C, Brack A (2012) Modulation of tight junction proteins in the perineurium to facilitate peripheral opioid analgesia. Anesthesiology 116(6): 1323-1334 (IF 5.4) [PubMed] [WebPage] [Full text via Ovid]
Previous work
Rittner HL*, Hackel D* (*shared first authorship), Voigt P, Mousa SA, Stolz A, Schaefer M, Schäfer M, Stein C, Brack A (2009) Mycobacteria attenuate nociceptive responses by formyl peptide receptor triggered opioid peptide release from neutrophils. PLoS Pathogens 5(4): e1000362.
Rittner HL, Hackel D, Yamdeu RS, Mousa SA, Stein C, Schäfer M, Brack A (2009) Endogenous opioid antinociception in noninflamed tissue - role of hypertonicity and the perineurium. Brain Behav. Immun. 23: 548-557.
Labuz D, Schmidt Y, Schreiter A, Rittner HL, Mousa SA, Machelska H (2009) Immune cell derived opioid protect against neuropathic pain. J. Clin. Invest. 119: 278-286.
Zöllner C, Mousa SA, Fischer O, Rittner HL, Shaqura M, Brack A, Urban F, Shakibaei M, Stein C, Schäfer M (2008) Inflammatory pain prevents the development of tolerance at peripheral µ-opioid receptors J. Clin. Invest. 118: 1065-1073.
Rittner HL, Lux C, Labuz D, Mousa SA , Schäfer M, Stein C, Brack A (2007) Neu-rokinin-1 receptor antagonists inhibit the recruitment of opioid-containing leukocytes and impair peripheral antinociception. Anesthesiology 107: 1009-1017.
Rittner HL, Labuz D, Richter JF, Brack A, Schäfer M, Stein C, Mousa SA (2007) Inhibition of inflammatory pain by CXCR1/2 ligands requires p38 MAPK activation and release of opioid peptide-containing primary granules from polymorphonuclear cells. Brain. Behav. Immun. 21: 1021-1032.
Rittner HL, Labuz D, Schaefer M, Mousa SA, Schulz S, Schäfer M, Stein C, Brack A (2006) Pain control by CXCR2 ligands through Ca2+-regulated release of opioid peptides from polymorphonuclear cells. FASEB J. 20(14): 2627-2629.
Rittner HL, Mousa SA, Labuz D, Beschmann K, Schäfer M, Stein C, Brack A (2006) Selective local PMN recruitment by CXCL1- or CXCL2/3-injection does not cause inflammatory pain. J. Leuk. Biol. 79(5): 1022-1032.
Labuz D, Berger, S, Mousa SA, Zöllner C, Rittner HL, Shaqura M, Przewlocka B, Stein C, Machelska H (2006) Peripheral antinociceptive effects of exogenous and immune cell-derived endomorphins in prolonged inflammatory pain. J. Neurosci. 26(16): 4350-4358.
Sitte N, Busch M, Mousa SA, Labuz D, Rittner HL, Gore C, Krause H, Stein C, Schäfer M (2006) Lymphocytes upregulate signal sequence-encoding proopiomelanocortin mRNA and beta-endorphin during painful inflammation in vivo. J. Neuroimmunol. 183: 133-145.
Pühler W*, Rittner HL* (*shared first authorship), Mousa SA, Brack A, Stein C, Schäfer M (2006) Interleukin-1 beta contributes to the upregulation of kappa opioid receptor mRNA in dorsal root ganglia in response to peripheral inflammation. Neuroscience 141(2): 989-998.*shared first aithorship
Brack A, Rittner HL, Machelska H, Leder K, Mousa SA, Schäfer M, Stein C (2004) Control of inflammatory pain by chemokine-mediated recruitment of opioid-containing polymorphonuclear cells. Pain 112 (3): 229-238.
Brack A, Rittner HL, Machelska H, Shaqura M, Mousa SA, Labuz D, Zöllner C, Schäfer M, Stein C (2004) Endogenous peripheral antinociception in early inflammation is not limited by the number of opioid-containing leukocytes but by opioid receptor expression. Pain 108 (1-2): 67-75.
Brack A, Labuz D, Schiltz A, Rittner HL, Machelska H, Schäfer M, Reszka R, Stein C (2004) Tissue monocytes/macrophages in inflammation: hyperalgesia versus opioid-mediated peripheral antinociception. Anesthesiology 101(1): 204-211.
Brack A, Rittner HL, Machelska H, Beschmann K, Sitte N, Schäfer M, Stein C (2004) Mobilization of opioid-containing polymorphonuclear cells by hematopoetic growth factors and influence on inflammatory pain. Anesthesiology 100: 149-157.
Machelska H, Brack A, Mousa SA, Schopohl JK, Rittner HL, Schäfer M, Stein C (2004) Selectins and integrins, but not platelet-endothelial cell adhesion molecule-1 regulate opioid inhibition of inflammatory pain. Br. J. Pharmacol. 142(4): 772-780.
Schrader M, Weissbach L, Müller M, Straub B, Krause H, Goessl C, Schostak M, Rittner HL, Stange S, Miller K (2004) Detection of germ-cell-tumor-specific gene products in peripheral blood by immunomagnetic tumor cell enrichment followed by RT-PCR. Int. J. Mol. Med. 13(5): 685-690.