title: Spinal matrix metalloproteinase 3 mediates inflammatory hyperalgesia via a tumor necrosis factor-dependent mechanism.
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.
authors: Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, MC 0818, La Jolla, CA 92093-0818, USA.
authors: C A
authors: CA
authors: Christianson
authors: B L
authors: BL
authors: Fitzsimmons
authors: J-H
authors: JH
authors: Shim
authors: A
authors: A
authors: Agrawal
authors: S M
authors: SM
authors: Cohen
authors: X-Y
authors: XY
authors: Hua
authors: T L
authors: TL
authors: Yaksh
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004151:Dipeptides / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D000068800:Etanercept; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006877:Hydroxamic Acids / Q000627:therapeutic use; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D007074:Immunoglobulin G / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D008070:Lipopolysaccharides; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000008:administration & dosage / Q000378:metabolism*; D008840:Microfilament Proteins; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D013449:Sulfonamides / Q000627:therapeutic use; D013997:Time Factors; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: C112986:AIF1 protein, human; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D004151:Dipeptides; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D006877:Hydroxamic Acids; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; C500716:N-isobutyl-N-(4-methoxyphenylsulfonyl)glycylhydroxamic acid; D018124:Receptors, Tumor Necrosis Factor; D013449:Sulfonamides; D048069:Tumor Necrosis Factors; D019278:Matrix Metalloproteinase 3; D000068800:Etanercept