Reciprocal relationship between membrane type 1 matrix metalloproteinase and the algesic peptides of myelin basic protein contributes to chronic neuropathic pain.
Myelin basic protein (MBP) is an auto-antigen able to induce intractable pain from innocuous mechanical stimulation (mechanical allodynia). The mechanisms provoking this algesic MBP activity remain obscure. Our present study demonstrates that membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14) releases the algesic MBP peptides from the damaged myelin, which then reciprocally enhance the expression of MT1-MMP in nerve to sustain a state of allodynia. Specifically, MT1-MMP expression and activity in rat sciatic nerve gradually increased starting at day 3 after chronic constriction injury (CCI). Inhibition of the MT1-MMP activity by intraneural injection of the function-blocking human DX2400 monoclonal antibody at day 3 post-CCI reduced mechanical allodynia and neuropathological signs of Wallerian degeneration, including axon demyelination, degeneration, edema and formation of myelin ovoids. Consistent with its role in allodynia, the MT1-MMP proteolysis of MBP generated the MBP69-86-containing epitope sequences in vitro. In agreement, the DX2400 therapy reduced the release of the MBP69-86 epitope in CCI nerve. Finally, intraneural injection of the algesic MBP69-86 and control MBP2-18 peptides differentially induced MT1-MMP and MMP-2 expression in the nerve. With these data we offer a novel, self-sustaining mechanism of persistent allodynia via the positive feedback loop between MT1-MMP and the algesic MBP peptides. Accordingly, short-term inhibition of MT1-MMP activity presents a feasible pharmacological approach to intervene in this molecular circuit and the development of neuropathic pain.
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, La Jolla, CA, USA; Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, Catholic University of Korea, Seoul, South Korea.
Sanghyun
S
Hong
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Albert G
AG
Remacle
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Sergei A
SA
Shiryaev
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, La Jolla, CA, USA; Department of Anesthesiology and Pain Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul, South Korea.
Wonjun
W
Choi
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, La Jolla, CA, USA.
Swathi K
SK
Hullugundi
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, La Jolla, CA, USA.
Jennifer
J
Dolkas
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, La Jolla, CA, USA.
Mila
M
Angert
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, La Jolla, CA, USA.
Tasuku
T
Nishihara
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA.
Tony L
TL
Yaksh
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Alex Y
AY
Strongin
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, La Jolla, CA, USA. Electronic address: vshubayev@ucsd.edu.
Veronica I
VI
Shubayev
D000818:Animals; D005260:Female; D006930:Hyperalgesia / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism*; D009437:Neuralgia / Q000378:metabolism*; D010455:Peptides; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000293:injuries
D004676:Myelin Basic Protein; D010455:Peptides; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1; D053511:Matrix Metalloproteinase 14
Allodynia; MBP; MMP; Myelin; Neuropathic pain; Peripheral nerve