MMPs initiate Schwann cell-mediated MBP degradation and mechanical nociception after nerve damage

Abstract

Matrix metalloproteinases (MMPs) emerge as modulators of neuropathic pain. Because myelin protects Aβ 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.

Time-Dependent Cross Talk between Spinal Serotonin 5-HT2AReceptor and mGluR1 Subserves Spinal Hyperexcitability and Neuropathic Pain after Nerve Injury

“…9) is in keeping with other studies (Röyttä et al, 1999;Sinnott et al, 1999;Clayton et al, 2007;Kaku et al, 2007;Kobayashi et al, 2008;Pérez-Severiano et al, 2008;Wei et al, 2010). In addition, the development of milder contralateral changes over Ͼ1 week as found here (Fig.…”

NADPH Oxidase-4 Maintains Neuropathic Pain after Peripheral Nerve Injury

“…In response to peripheral nerve injury, myelinating Schwann cells are activated and their myelin properties are modified, resulting in altered conduction properties of nociceptive fibers (Devor, 2006b;Thacker et al, 2007;Nagai et al, 2010). In particular, the myelin degradation of A␤ afferents promotes susceptibility of their axonal plasma membrane to pronociceptive stimuli, leading to ectopic depolarization and mechanical allodynia (Kobayashi et al, 2008). Accordingly, neuropathic pain behaviors occurred after experimental demyelination of peripheral or central neurons (Wallace et al, 2003;Inoue et al, 2004;Moalem-Taylor et al, 2007;Zhu et al, 2012) and in mutant mice with aberrant myelination or loss of myelin (Gillespie et al, 2000;Chen et al, 2006).…”

SNO-ing at the Nociceptive Synapse?

“…Inhibition of either MMP-9 or MMP-2 resulted in a reduction of nociceptive responses after sciatic nerve injury, partially mediated by blocking interleukin-1␤ cleavage and glia activation (Kawasaki et al, 2008). Short-and long-term therapy with a broad-spectrum MMP inhibitor also protected from injury-induced myelin basic protein degradation, caspase-mediated apoptosis, macrophage infiltration, and astrocyte activation in the spinal cord (Kobayashi et al, 2008). This suggests that the activation of metalloproteinases by S-nitrosylation may constitute an essential step in the reorganization and adaptive processes that, after nerve injury, pioneer the restitution of function, possibly at the expense of temporary enhanced nociceptive sensitivity.…”