MMPs initiate Schwann cell-mediated MBP degradation and mechanical nociception after nerve damage.
Matrix metalloproteinases (MMPs) emerge as modulators of neuropathic pain. Because myelin protects Abeta afferents from ectopic hyperexcitability and nociception from innocuous mechanical stimuli (or mechanical allodynia), we analyzed the role of MMPs in the development of mechanical allodynia through myelin protein degradation after rat and MMP-9-/- mouse L5 spinal nerve crush (L5 SNC). MMPs were shown to promote selective degradation of myelin basic protein (MBP), with MMP-9 regulating initial Schwann cell-mediated MBP processing after L5 SNC. Acute and long-term therapy with GM6001 (broad-spectrum MMP inhibitor) protected from injury-induced MBP degradation, caspase-mediated apoptosis, macrophage infiltration in the spinal nerve and inhibited astrocyte activation in the spinal cord. The effect of GM6001 therapy on attenuation of mechanical allodynia was robust, immediate and sustained through the course of L5 SNC. In conclusion, MMPs mediate the initiation and maintenance of mechanical nociception through Schwann cell-mediated MBP processing and support of neuroinflammation.
Kobayashi
Hideo
H
Department of Anesthesiology, University of California, San Diego, CA 92093-0629, USA.
Chattopadhyay
Sharmila
S
Kato
Kinshi
K
Dolkas
Jennifer
J
Kikuchi
Shin-Ichi
S
Myers
Robert R
RR
Shubayev
Veronica I
VI
D000818:Animals; D017209:Apoptosis; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival; D004151:Dipeptides / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism*; D009409:Nerve Crush; D009457:Neuroglia / Q000378:metabolism; D010146:Pain / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010147:Pain Measurement; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism*; D013127:Spinal Nerves / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; D004676:Myelin Basic Protein; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9