Elsevier

Experimental Neurology

Volume 258, August 2014, Pages 48-61
Experimental Neurology

Review
Neuroinflammatory contributions to pain after SCI: Roles for central glial mechanisms and nociceptor-mediated host defense

https://doi.org/10.1016/j.expneurol.2014.02.001Get rights and content

Highlights

  • Current treatments for neuropathic SCI pain are inadequate and not based on well understood mechanisms.

  • In animal models several interventions targeting neuroinflammation are effective in reducing behavioral indices of SCI pain.

  • Effective interventions for SCI pain include inhibitors of activity in microglia, astroglia, and primary nociceptors.

  • Promotion of central neuroinflammation by sensitized nociceptors suggests new targets and complexities in treating SCI pain

Abstract

Neuropathic pain after spinal cord injury (SCI) is common, often intractable, and can be severely debilitating. A number of mechanisms have been proposed for this pain, which are discussed briefly, along with methods for revealing SCI pain in animal models, such as the recently applied conditioned place preference test. During the last decade, studies of animal models have shown that both central neuroinflammation and behavioral hypersensitivity (indirect reflex measures of pain) persist chronically after SCI. Interventions that reduce neuroinflammation have been found to ameliorate pain-related behavior, such as treatment with agents that inhibit the activation states of microglia and/or astroglia (including IL-10, minocycline, etanercept, propentofylline, ibudilast, licofelone, SP600125, carbenoxolone). Reversal of pain-related behavior has also been shown with disruption by an inhibitor (CR8) and/or genetic deletion of cell cycle-related proteins, deletion of a truncated receptor (trkB.T1) for brain-derived neurotrophic factor (BDNF), or reduction by antisense knockdown or an inhibitor (AMG9810) of the activity of channels (TRPV1 or Nav1.8) important for electrical activity in primary nociceptors. Nociceptor activity is known to drive central neuroinflammation in peripheral injury models, and nociceptors appear to be an integral component of host defense. Thus, emerging results suggest that spinal and systemic effects of SCI can activate nociceptor-mediated host defense responses that interact via neuroinflammatory signaling with complex central consequences of SCI to drive chronic pain. This broader view of SCI-induced neuroinflammation suggests new targets, and additional complications, for efforts to develop effective treatments for neuropathic SCI pain.

Introduction

While our everyday experiences with acute inflammation highlight the close association between inflammation and pain, it is only within the last decade that investigators have linked neuroinflammatory consequences of SCI to the life-long, intractable pain that many SCI patients endure. Neuroinflammation refers to the inflammatory responses of the nervous system to pathogens, trauma, toxins, or neurodegeneration. The realization that widespread neuroinflammation plays a major role in driving neuropathic pain after SCI has been accompanied by discoveries of unexpected overlap of neuroinflammatory mechanisms that drive persistent pain after both injuries to the central nervous system and to peripheral tissues. This review discusses experimental evidence and a new conceptual perspective that provide insight into how neuroinflammation contributes to SCI pain. Although progress in developing effective treatments for neuropathic SCI pain has been slow, a number of recent preclinical findings suggest novel therapeutic targets that may offer promise as additional treatment options.

Section snippets

Prevalence, types, and properties of pain after SCI

Estimates of its prevalence vary greatly, but it is likely that chronic pain afflicts a majority of SCI patients (Dijkers et al., 2009). This pain is typically divided into two major classes, nociceptive and neuropathic (Bryce et al., 2012). The largest prospective pain study of patients with traumatic SCI found that moderate-to-severe nociceptive and neuropathic pain was equally common (each affecting 59% of patients) one year after SCI (Finnerup et al., 2014). A third class, “other pain,” is

The use of animal models to study mechanisms of neuropathic SCI pain

As mentioned in other articles in this special issue, SCI is always followed by neuroinflammation. Clinical observations, including chronic elevation of proinflammatory cytokines in the CSF and blood of patients (Davies et al., 2007, Hayes et al., 2002, Kwon et al., 2010, Segal et al., 1997, Stein et al., 2013), are consistent with the possibility that neuroinflammation that may promote pain persists long after SCI, but direct mechanistic studies in patients have not been performed. The most

Types of mechanisms implicated in neuropathic SCI pain

Neuroinflammatory mechanisms are just one set of mechanisms driving SCI pain, and will be reviewed in the following sections. Other general mechanisms have also been proposed, and these may operate independently or synergistically with neuroinflammation to promote SCI pain. Some of these represent direct effects of injury on spinal tissue. An immediate effect of spinal injury is intense activation of nearby neurons by depolarizing agents released during the injury (e.g., K + and glutamate from

Why spinal neuroinflammation should produce neuropathic SCI pain

Neuroinflammation is commonly and simply defined as an inflammation of part of the nervous system. Inflammation is classically defined as a coordinated response of the innate immune system that combats infection. The relatively primitive innate immune system is the first line of defense against pathogens and toxins; it is always present and it depends upon diverse cell types that include barrier cells, phagocytes, and various parenchymal cells in different tissues, including the nervous system.

Is neuropathic SCI pain driven by a unified host defense system?

An implicit assumption guiding most work on neuropathic SCI pain is that the pain arises in a disorganized fashion from any of numerous, often independent effects of the injury on different components of pain pathways (see section above on classes of mechanisms). An interesting possibility is that SCI also inadvertently activates integrated response systems that employ pain and neuroinflammation as part of host defense against pathogens, parasites, and other threats. It has long been

Implications of neuroinflammatory mechanisms for treating neuropathic SCI pain

No front-line treatments currently used for neuropathic SCI pain specifically target neuroinflammatory mechanisms, although some probably do so indirectly. Standard treatments for SCI pain are based on those commonly (and with only limited success) used for peripheral neuropathic pain, notably the anticonvulsants gabapentin and pregabalin, and antidepressants such as amitriptyline, although many other drugs are used, including other serotonin–norepinephrine reuptake inhibitors, opioids, and

Conclusions

While multiple mechanisms contribute to neuropathic pain after SCI, numerous experimental observations indicate that persistent neuroinflammation is critical for the development and maintenance of this pain. Most of these observations are recent; only within the last decade has it become clear that neuroinflammation after SCI is chronic (perhaps permanent) and that interventions that target persistent neuroinflammation ameliorate behavioral hypersensitivity in animal models of neuropathic SCI

Acknowledgments

ETW acknowledges the support from the Department of Defense USAMRAA, Craig Neilsen Foundation, Mission Connect/TIRR, and National Science Foundation during the preparation of this article.

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