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

Abstract

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. Mechanisms of neuropathic pain are incompletely known. Neural mechanisms of neuropathic pain have been extensively investigated over several decades. It is generally believed that neuropathic pain manifests as an expression of neural plasticity both in the PNS (peripheral sensitization) and CNS (central sensitization). Central sensitization in spinal cord dorsal horn neurons is particularly important for the persistence of neuropathic pain and spread of pain beyond the initial injury site. Central sensitization in dorsal horn neurons can be induced both by an increase in excitatory synaptic transmission mediated via the glutamate NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and a decrease or loss of inhibitory synaptic transmission (disinhibition) mediated via gamma-aminobutyric acid (GABA) and glycine receptors. 2 Increasing evidence has also suggested glial mechanisms of neuropathic pain. Nerve injury induces a profound activation of glial cells such as microglia and astrocytes in the spinal cord, and the activated glia can release multiple pain mediators to enhance neuropathic pain via glial–neural interaction. 1,5,6 For example, peripheral nerve injury induces very dramatic changes in spinal cord microglia and astrocytes, including morphological changes, proliferation, and upregulation of the glial markers (e.g. CD11b/OX-42, Iba1, and glial fibrillary acidic protein [GFAP]). Several glial inhibitors, such as flurocitrate, alpha-aminoadipate, minocycline, and propentofylline, have been shown to attenuate neuropathic pain. 5,7 In particular, mitogen-activated protein kinases (MAPKs) are activated in glial cells after nerve injury and serve as critical signaling molecules in glia for neuropathic pain sensitization. MAPK activation in glial cells may lead to the production of inflammatory mediators such as prostaglandins, cytokines, and chemokines, as well as growth factors, to enhance and maintain neuropathic pain.