Abstract
Matrix metalloproteinases (MMPs) have been implicated in the modulation of synaptic plasticity, glial activation, and long-term potentiation in the CNS. Here we demonstrate for the first time a mechanism for the regulation of nociceptive processing by spinal MMP-3 during peripheral inflammation. We first determined by western blotting that the catalytic (active) form of MMP-3 (cMMP-3) is increased in lumbar spinal cord following peripheral inflammation in rats. The peripheral inflammation-induced thermal hyperalgesia and tactile hypersensitivity was transiently (2-3 h) attenuated by intrathecal (IT) pretreatment with either an MMP-3 inhibitor (NNGH), or a broad spectrum MMP inhibitor (GM6001). In addition, IT delivery of cMMP-3 evoked hypersensitivity, whereas the pro (enzymatically inactive) form of MMP-3 did not. This suggests a pro-algesic effect of spinal MMP-3 mediated by an enzymatic mechanism. This cMMP-3-induced hypersensitivity is concurrent with increased tumor necrosis factor (TNF) in the spinal cord. The hypersensitivity behavior is prevented by intrathecal etanercept (TNF blockade). Treatment with cMMP-3 resulted in an increase in TNF release from spinal primary microglial, but not astrocyte cultures. These findings thus present direct evidence implicating MMP-3 in the coordination of spinal nociceptive processing via a spinal TNF-dependent mechanism.
Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Analysis of Variance
-
Animals
-
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
-
Calcium-Binding Proteins
-
Cells, Cultured
-
DNA-Binding Proteins / metabolism
-
Dipeptides / therapeutic use
-
Disease Models, Animal
-
Dose-Response Relationship, Drug
-
Enzyme Inhibitors / therapeutic use
-
Enzyme-Linked Immunosorbent Assay / methods
-
Etanercept
-
Gene Expression Regulation / drug effects
-
Glial Fibrillary Acidic Protein / metabolism
-
Hydroxamic Acids / therapeutic use
-
Hyperalgesia / drug therapy
-
Hyperalgesia / etiology
-
Hyperalgesia / pathology*
-
Immunoglobulin G / therapeutic use
-
Inflammation / chemically induced
-
Inflammation / complications
-
Lipopolysaccharides
-
Male
-
Matrix Metalloproteinase 3 / administration & dosage
-
Matrix Metalloproteinase 3 / metabolism*
-
Microfilament Proteins
-
Neuroglia / drug effects
-
Neuroglia / metabolism
-
Pain Measurement
-
Pain Threshold / drug effects
-
Pain Threshold / physiology*
-
Physical Stimulation
-
Rats
-
Rats, Sprague-Dawley
-
Reaction Time / drug effects
-
Receptors, Tumor Necrosis Factor / therapeutic use
-
Spinal Cord / drug effects
-
Spinal Cord / enzymology*
-
Spinal Cord / pathology
-
Sulfonamides / therapeutic use
-
Time Factors
-
Tumor Necrosis Factors / metabolism*
Substances
-
AIF1 protein, human
-
Anti-Inflammatory Agents, Non-Steroidal
-
Calcium-Binding Proteins
-
DNA-Binding Proteins
-
Dipeptides
-
Enzyme Inhibitors
-
Glial Fibrillary Acidic Protein
-
Hydroxamic Acids
-
Immunoglobulin G
-
Lipopolysaccharides
-
Microfilament Proteins
-
N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide
-
N-isobutyl-N-(4-methoxyphenylsulfonyl)glycylhydroxamic acid
-
Receptors, Tumor Necrosis Factor
-
Sulfonamides
-
Tumor Necrosis Factors
-
Matrix Metalloproteinase 3
-
Etanercept