ArticleProceedings of the National Academy of Sciences of the United States of America2012
Transient opening of the perineurial barrier for analgesic drug delivery.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 1 of them a synthesis that pooled it.
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Who cites it
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 90 citations in OpenAlex.
- FcRn as a Transporter for Nasal Delivery of Biologics: A Systematic Review.International journal of molecular sciences · 2021Pooled it
- Modulation of antibody transport in the brain and spinal cord through the intranasal pathway.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- The role and mechanisms of matrix metalloproteinase-9 in peripheral neuropathic pain.Frontiers in molecular neuroscience · 2025Review
- TAM receptors mediate the Fpr2-driven pain resolution and fibrinolysis after nerve injury.Acta neuropathologica · 2024Article
- Therapeutic Implication of miRNAs as an Active Regulatory Player in the Management of Pain: A Review.Genes · 2024Review
- Article
- Miniaturized therapeutic systems for ultrasound-modulated drug delivery to the central and peripheral nervous system.Advanced drug delivery reviews · 2024Review
- Drug Permeability: From the Blood-Brain Barrier to the Peripheral Nerve Barriers.Advanced therapeutics · 2023Article
- Selective Targeting of Nav1.7 with Engineered Spider Venom-Based Peptides.Channels (Austin, Tex.) · 2021Review
- Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury.International journal of molecular sciences · 2021Article
- Selective blood-nerve barrier leakiness with claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy.Journal of molecular medicine (Berlin, Germany) · 2021Article
- Liposomal Bupivacaine (Bupigel) Demonstrates Minimal Local Nerve Toxicity in a Rabbit Functional Model.Pharmaceutics · 2021Article
- Morphine Suppresses Liver Cancer Cell Tumor PropertiesFrontiers in oncology · 2021Article
- Targeting the blood-nerve barrier for the management of immune-mediated peripheral neuropathies.Experimental neurology · 2020Review
- Regional Differences in Tight Junction Protein Expression in the Blood-DRG Barrier and Their Alterations after Nerve Traumatic Injury in Rats.International journal of molecular sciences · 2019Article
- Multipotent vascular stem cells contribute to neurovascular regeneration of peripheral nerve.Stem cell research & therapy · 2019Article
- Intracerebroventricular Coadministration of Protoxin-II and Trace Elements in Rats Enhances the Analgesic Effect of the 1.7 Voltage-Gate Sodium Channel Blocker.BioMed research international · 2019Article
- Delivery of immunoglobulin G antibodies to the rat nervous system following intranasal administration: Distribution, dose-response, and mechanisms of delivery.Journal of controlled release : official journal of the Controlled Release Society · 2018Article
- Antinociception by the anti-oxidized phospholipid antibody E06.British journal of pharmacology · 2018Article
- High-frequency, low-intensity ultrasound and microbubbles enhance nerve blockade.Journal of controlled release : official journal of the Controlled Release Society · 2018Article
Corrections and comments
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Authors and funding
19 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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