Spinal matrix metalloproteinase 3 mediates inflammatory hyperalgesia via a tumor necrosis factor-dependent mechanism

Neuroscience. 2012 Jan 3:200:199-210. doi: 10.1016/j.neuroscience.2011.10.019. Epub 2011 Oct 20.

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.

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