Transient opening of the perineurial barrier for analgesic drug delivery.
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.
Department of Anesthesiology, University Hospitals Wurzburg, Julius Maximilians University, 97080 Würzburg, Germany.
Dagmar
D
Hackel
Susanne M
SM
Krug
Reine-Solange
RS
Sauer
Shaaban A
SA
Mousa
Alexander
A
Böcker
Diana
D
Pflücke
Esther-Johanna
EJ
Wrede
Katrin
K
Kistner
Tali
T
Hoffmann
Benedikt
B
Niedermirtl
Claudia
C
Sommer
Laura
L
Bloch
Otmar
O
Huber
Ingolf E
IE
Blasig
Salah
S
Amasheh
Peter W
PW
Reeh
Michael
M
Fromm
Alexander
A
Brack
Heike L
HL
Rittner
D000700:Analgesics / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D062445:Claudin-1; D058266:Dielectric Spectroscopy; D016503:Drug Delivery Systems / Q000379:methods*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism* / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects; D010525:Peripheral Nerves / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D012462:Saline Solution, Hypertonic / Q000008:administration & dosage* / Q000378:metabolism
D000700:Analgesics; D062445:Claudin-1; C568114:Cldn1 protein, rat; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D012462:Saline Solution, Hypertonic; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9