Document Detail


Transient opening of the perineurial barrier for analgesic drug delivery.
MedLine Citation:
PMID:  22733753     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Selective targeting of sensory or nociceptive neurons in peripheral nerves remains a clinically desirable goal. Delivery of promising analgesic drugs is often impeded by the perineurium, which functions as a diffusion barrier attributable to tight junctions. We used perineurial injection of hypertonic saline as a tool to open the perineurial barrier transiently in rats and elucidated the molecular action principle in mechanistic detail: Hypertonic saline acts via metalloproteinase 9 (MMP9). The noncatalytic hemopexin domain of MMP9 binds to the low-density lipoprotein receptor-related protein-1, triggers phosphorylation of extracellular signal-regulated kinase 1/2, and induces down-regulation of the barrier-forming tight junction protein claudin-1. Perisciatic injection of any component of this pathway, including MMP9 hemopexin domain or claudin-1 siRNA, enables an opioid peptide ([D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin) and a selective sodium channel (NaV1.7)-blocking toxin (ProToxin-II) to exert antinociceptive effects without motor impairment. The latter, as well as the classic TTX, blocked compound action potentials in isolated nerves only after disruption of the perineurial barrier, which, in return, allowed endoneurally released calcitonin gene-related peptide to pass through the nerve sheaths. Our data establish the function and regulation of claudin-1 in the perineurium as the major sealing component, which could be modulated to facilitate drug delivery or, potentially, reseal the barrier under pathological conditions.
Authors:
Dagmar Hackel; Susanne M Krug; Reine-Solange Sauer; Shaaban A Mousa; Alexander Böcker; Diana Pflücke; Esther-Johanna Wrede; Katrin Kistner; Tali Hoffmann; Benedikt Niedermirtl; Claudia Sommer; Laura Bloch; Otmar Huber; Ingolf E Blasig; Salah Amasheh; Peter W Reeh; Michael Fromm; Alexander Brack; Heike L Rittner
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-06-25
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-18     Completed Date:  2012-10-11     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E2018-27     Citation Subset:  IM    
Affiliation:
Department of Anesthesiology, University Hospitals Wurzburg, Julius Maximilians University, 97080 Würzburg, Germany.
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MeSH Terms
Descriptor/Qualifier:
Analgesics / administration & dosage*,  metabolism
Animals
Blotting, Western
Claudin-1
Dielectric Spectroscopy
Drug Delivery Systems / methods*
Extracellular Signal-Regulated MAP Kinases / metabolism
Fluorescent Antibody Technique
Gene Expression Regulation / drug effects*
Matrix Metalloproteinase 9 / metabolism*,  pharmacology
Membrane Proteins / metabolism
Pain Threshold / drug effects
Peripheral Nerves / metabolism*
Phosphorylation
RNA, Small Interfering / genetics
Rats
Saline Solution, Hypertonic / administration & dosage*,  metabolism
Chemical
Reg. No./Substance:
0/Analgesics; 0/Claudin-1; 0/Cldn1 protein, rat; 0/Membrane Proteins; 0/RNA, Small Interfering; 0/Saline Solution, Hypertonic; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 3.4.24.35/Matrix Metalloproteinase 9
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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