MMP-2 and MMP-9—Investigations in Neuropathic Pain Phases

MMP-2 and MMP-9—Investigations in Neuropathic Pain Phases

Ji Ru-Rong, Lo Eng H, Wang Xiaoying, Xu Zhen-Zhong
Published: US Neurology - Volume 4 Issue 2
download article

| More
dots

Management of neuropathic pain is a real clinical challenge. Current treatments focus on blocking neurotransmission and do not differentiate between different phases of neuropathic pain pathophysiology. The authors have recently shown that nerve-injury-induced neuropathic pain development requires matrix metalloprotease-9 and -2 (MMP-9 and MMP- 2) in the early and late phase, respectively. Inhibition of MMP-9 or MMP-2 may provide a novel therapeutic approach for the treatment of neuropathic pain at different phases.

Neuropathic Pain Symptoms and Mechanisms
Many patients in the pain clinic suffer from neuropathic pain due to injury to the peripheral nervous system (PNS) (e.g. peripheral nerves) or the central nervous system (CNS) (e.g. spinal cord and thalamus). These injuries may result from major surgeries (e.g. amputation and thoracotomy), diabetic neuropathy, viral infection, chemotherapy, spinal cord injury, stroke, and so forth. Although neuropathic pain in animal models after specific nerve injury is highly reproducible, only a portion of patients after nerve injuries will develop neuropathic pain, depending on genetic background and medical history.1 Neuropathic pain is often characterized by spontaneous pain, described as shooting, lancinating, or burning pain, and also by evoked pain, such as hyperalgesia (increased responsiveness to noxious stimuli) to mechanical and thermal stimuli. Probably the most distinct symptom of neuropathic pain is mechanical allodynia (painful responses to normally innocuous tactile stimuli). For example, patients feel enormous pain during movement. Currently available drugs such as tricyclic antidepressants, anticonvulsants, sodium channel blockers, N-methyl-D-aspartate (NMDA) receptor antagonists, and opioids provide relief from neuropathic pain in only a fraction of such patients, with severe side effects.2,3 This failure results in part from the strategy of these drugs to block neurotransmission, ignoring the underlying pathology of neuropathic pain. Therefore, pain relief after many treatments often lasts no longer than the drug’s presence at the site.

Neuropathic pain research has been accelerated with different animal models in which the sciatic nerve and its branches, or the spinal nerves, or the spinal cord are intentionally damaged.1,4 How well these different injury models include the clinically presenting pain syndromes remains an important concern for validating common mechanisms and establishing animal models for human drug testing. However, clinical cases are often difficult to study because there are multiple contributing factors and the time from the initial insult, when it is recognized, can vary from several days, to weeks, to years. Thus, most mechanistic studies are based on animal models.

123456next ›last »
References:
  1. Ji RR, Strichartz G. Cell signaling and the genesis of neuropathic pain, Sci STKE, 2004;reE14.
  2. Woolf CJ, Mannion RJ, Neuropathic pain: aetiology, symptoms, mechanisms, and management, Lancet, 1999;353:1959–64.
  3. Kehlet H, Jensen TS, Woolf CJ, Persistent postsurgical pain: risk factors and prevention, Lancet, 2006;367:1618–25.
  4. Kim SH, Chung JM, An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat, Pain, 1992;50:355–63.
  5. Watkins LR, Milligan ED, Maier SF, Glial activation: a driving force for pathological pain, Trends Neurosci, 2001;24:450–55.
  6. Tsuda M, Inoue K, Salter MW, Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia, Trends Neurosci, 2005;28:101–7.
  7. Raghavendra V, Tanga F, DeLeo JA, Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy, J Pharmacol Exp Ther, 2003;306:624–30.
  8. Jin SX, Zhuang ZY, Woolf CJ, Ji RR, p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain, J Neurosci, 2003;23:4017–22.
  9. Zhuang ZY, Wen YR, Zhang DR, et al., A peptide c-Jun Nterminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance, J Neurosci, 2006;26:3551–60.
  10. Zhuang ZY, Gerner P, Woolf CJ, Ji RR, ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model, Pain, 2005;114:149–59.
  11. Sweitzer S, Martin D, DeLeo JA, Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain, Neuroscience, 2001;103:529–39.
  12. Kawasaki Y, Zhang L, Cheng JK, Ji RR, Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord, J Neurosci, 2008;28(20):5189–94.
  13. Schonbeck U, Mach F, Libby P, Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1- independent pathway of IL-1 beta processing, J Immunol, 1998;161:3340–46.
  14. Fantuzzi G, Ku G, Harding MW, et al., Response to local inflammation of IL-1 beta-converting enzyme- deficient mice, J Immunol, 1997;158:1818–24.
  15. Yong VW, Metalloproteinases: mediators of pathology and regeneration in the CNS, Nat Rev Neurosci, 2005;6:931–44.
  16. Rosenberg GA, Matrix metalloproteinases in neuroinflammation, Glia, 2002;39:279–91.
  17. Parks WC, Wilson CL, Lopez-Boado YS, Matrix metalloproteinases as modulators of inflammation and innate immunity, Nat Rev Immunol, 2004;4:617–29.
  18. Chattopadhyay S, Myers RR, Janes J, Shubayev V, Cytokine regulation of MMP-9 in peripheral glia: Implications for pathological processes and pain in injured nerve, Brain Behav Immun, 2007;21:561–8.
  19. Murphy G, Willenbrock F, Tissue inhibitors of matrix metalloendopeptidases, Methods Enzymol, 1995;248:496–510.
  20. Wang X, Jung J, Asahi M, et al., Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury, J Neurosci, 2000;20:7037–42.
  21. Zhao BQ, Wang S, Kim HY, et al., Role of matrix metalloproteinases in delayed cortical responses after stroke, Nat Med, 2006;12:441–5.
  22. Kawasaki Y, Xu ZZ, Wang X, et al., Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain, Nat Med, 2008;14(3):331–6.
  23. Murata Y, Rosell A, Scannevin RH, et al., Extension of the thrombolytic time window with minocycline in experimental stroke, Stroke, 2008 Oct 16 (Epub ahead of print).
  24. Yong VW, Wells J, Giuliani F, et al., The promise of minocycline in neurology, Lancet Neurol, 2004;3(12):744–51.
  25. Gordon PH, Moore DH, Miller RG, Fet al.; Western ALS Study Group, Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial, Lancet Neurol, 2007;6(12):1045–53.

Copyright® 2012 Touch Group PLC. All rights reserved.
Touch Neurology is for informational purposes and should not be considered medical advice, diagnosis or treatment recommendations.