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MMP-2 and MMP-9—Investigations in Neuropathic Pain Phases
21 days after SNL). SNL induces a rapid (less than one day) but transient Satellite cells in the DRG and astrocytes in the spinal cord share some
(more than three days) upregulation of MMP-9 in the DRG. Furthermore, similar features: they both show persistent upregulation of GFAP and pERK
MMP-9 expression increases in DRG neurons on day one.
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To define the after nerve injury and contribute to the maintenance of neuropathic pain.
specific role of MMP-9 in neuropathic pain development, the authors Of interest, MMP-9 is not necessary for MMP-2 upregulation, since SNL still
employed five different approaches: upregulates MMP-2 even in Mmp9 knockout mice.
• small synthetic inhibitor of MMP-9; To determine the role of MMP-2 in late-phase neuropathic pain, three
• endogenous peptide inhibitor of MMP-9 (TIMP-1); different pharmacological approaches were used:
• small interfering RNA against MMP-9;
• exogenous MMP-9 injection; and • small synthetic inhibitor of MMP-2;
• MMP-9 knockout mice. • endogenous peptide inhibitor of MMP-2 (TIMP-2); and
• small interfering RNA against MMP-2 to block MMP-2 in the late phase.
To avoid systemic effects of drugs, the authors delivered these drugs into
spinal fluid via intrathecal administration to target MMP-9 in the DRG and The data consistently show that MMP-2 inhibition can very effectively
spinal cord. Results from these five different approaches are very consistent, attenuate neuropathic pain in the late phase. In contrast, injection of
showing that MMP-9 inhibition or deletion can attenuate neuropathic pain exogenous MMP-2 is able to induce neuropathic pain symptoms.
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While
in the early phase. Conversely, intrathecal injection of exogenous MMP-9 is MMP-9 induces IL-1β cleavage and activation in the early phase, MMP-2
sufficient to induce mechanical allodynia. In particular, the endogenous appears to do this in the late phase. MMP-2 is also important for the
inhibitor TIMP-1 is 1,000 times more potent than morphine, a commonly activation of spinal cord astrocytes, since MMP-2 inhibition can suppress
used analgesic to treat neuropathic pain, and the duration of pain pERK induction in spinal cord astrocytes in the late phase.
22
Taken together,
suppression by TIMP-1 is also 10 times longer than that of morphine. MMP-2 contributes to late-phase neuropathic pain development by
However, this powerful inhibitor only works in the early phase (e.g. day activating IL-1β and astrocytes in the late phase.
one), not in the late phase (e.g. day 10).
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Clinical Significance and Future Directions
The authors have further explored the mechanisms by which MMP-9 Chronic pain affects more than 50 million Americans per year and is
induces neuropathic pain. SNL induces a marked IL-1β activation widely believed to represent a disease itself. In particular, neuropathic
(cleavage) in the DRG in the early phase (day one), which is lost in mice pain is very destructive and current treatments for this pain have only
lacking Mmp9, suggesting that MMP-9 is needed for IL-1β activation after resulted in limited success. This failure results, in part, from the following
nerve injury. Injection of MMP-9 is also sufficient to induce IL-1β activation reasons. First, our knowledge of neuropathic pain development and
in the DRG. Furthermore, MMP-9 and IL-1β are co-expressed in the same maintenance is incomplete and current treatments do not differentiate
neurons in the DRG.
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The authors hypothesize that nerve-injury-induced between different phases of neuropathic pain. Second, current
spontaneous discharge in sensory neurons can release MMP-9 and pro-IL- treatments often ignore the pathology of neuropathic pain and simply
1β into the ECM, where MMP-9 cleaves pro-IL-1β to produce active IL-1β. focus on blocking neurotransmission, producing only transient pain
The active IL-1β then acts on adjacent nociceptive neurons to produce relief. The authors’ studies suggest that MMP-9 inhibition may be used
hyperexcitability. The authors’ behavioral studies show that blocking IL-1β to prevent neuropathic pain induced after major surgeries (e.g.
with a neutralizing antibody can suppress neuropathic pain symptoms amputation, thoracotomy) and trauma (e.g. spinal cord injury), whereas
induced either by MMP-9 or by nerve injury, supporting an important role MMP-2 inhibition may be used to treat established neuropathic pain such
of the MMP-9/IL-1β cascade in neuropathic pain development. Finally, as diabetic neuropathy.
MMP-9 in DRG soma is transported to central terminals in the dorsal horn
to activate microglia. At the spinal level, MMP-9 is sufficient to activate MMPs belong to a very large family and they can activate each other. It
microglia even in a low dose that does not produce demyelination and is important to understand a network activation of different MMPs in
apoptosis.
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Collectively, MMP-9 induces early-phase neuropathic pain by neuropathic pain conditions. Different MMPs may play different roles in
activating IL-1β and microglia in the early phase. neuropathic pain. Thus, a broad inhibitor of MMPs may not be very
effective and will produce severe side effects, since MMPs are involved in
Matrix Metalloprotease-2 and Late-phase Neuropathic Pain tissue remodeling and wound healing.
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However, it is a real challenge to
Nerve injury also induces an upregulation of MMP-2, but the induction develop highly specific small synthetic inhibitors that only inhibit MMP-9
pattern of MMP-2 is quite different from that of MMP-9: or MMP-2. More specific targeting of MMP-9 or MMP-2 with monoclonal
antibodies, siRNAs, and peptide inhibitors may reduce the side effects of
• in contrast to a rapid and transient upregulation of MMP-9, SNL broad MMP inhibitors. Apart from IL-1β, MMP-9 and MMP-2 are likely to
produces a delayed (more than seven-day) and persistent (>21-day) cleave multiple substrates to promote neuropathic pain. It is important to
upregulation of MMP-2 in the DRG; investigate the potential substrates in the DRG and spinal cord tissues,
• while MMP-9 is induced in DRG neurons, MMP-2 is induced in small which may also lead to novel therapeutics by targeting the interaction
satellite cells surrounding DRG neurons; and between MMP-2/-9 and their substrates. Finally, the tetracycline
• although MMP-9 activity in the spinal cord is low even after nerve injury, minocycline is a relatively safe drug and has been proposed to treat
in part due to rapid release from central terminals, MMP-2 upregulation different types of neurological diseases. Of interest, minocycline is also
is persistently induced in spinal cord astrocytes.
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an inhibitor of MMP-9.
23,24
However, a recent clinical trial testing
US NEUROLOGY 73
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