Activated Microglia Contribute to the Maintenance of Chronic Pain after Spinal Cord Injury

By B. Hains, Stephen G. Waxman. Journal of Neuroscience, 2006

631 citations recorded by the source corpus.

Traumatic spinal cord injury (SCI) results not only in motor impairment but also in chronic central pain, which can be refractory to conventional treatment approaches. It has been shown recently that in models of peripheral nerve injury, spinal cord microglia can become activated and contribute to development of pain. Considering their role in pain after peripheral injury, and because microglia are known to become activated after SCI, we tested the hypothesis that activated microglia contribute to chronic pain after SCI. In this study, adult male Sprague Dawley rats underwent T9 spinal cord contusion injury. Four weeks after injury, when lumbar dorsal horn multireceptive neurons became hyperresponsive and when behavioral nociceptive thresholds were decreased to both mechanical and thermal stimuli, intrathecal infusions of the microglial inhibitor minocycline were initiated. Electrophysiological experiments showed that minocycline rapidly attenuated hyperresponsiveness of lumbar dorsal horn neurons. Behavioral data showed that minocycline restored nociceptive thresholds, at which time spinal microglial cells assumed a quiescent morphological phenotype. Levels of phosphorylated-p38 were decreased in SCI animals receiving minocycline. Cessation of delivery of minocycline resulted in an immediate return of pain-related phenomena. These results suggest an important role for activated microglia in the maintenance of chronic central below-level pain after SCI and support the newly emerging role of non-neuronal immune cells as a contributing factor in post-SCI pain.

Subfields: Cellular and Molecular Neuroscience, Pathology and Forensic Medicine, Physiology

View Paper: https://www.semanticscholar.org/paper/9d666b0fd1148e8222a706b7866ced7275b7a50e

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. R. Ji
2. M. Suter
3. A. Tran
4. P. Warren
5. J. Silver
6. Maiken Nedergaard
7. Oliver D. Howes
8. M. Malcangio

In Pathology and Forensic Medicine

1. R. Ji
2. M. Suter

In Physiology

1. M. Suter
2. T. Berta
3. Maiken Nedergaard
4. M. Malcangio
5. R. Gereau
6. G. Strichartz
7. R. Ji
8. Clifford J. Woolf

Citations in the corpus

• p38 MAPK, microglial signaling, and neuropathic pain (2007, background): “Minocycline also inhibits spinal p38 activation in a neuropathic pain condition [40].”
• Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. (2008, background): “Similarly, the antibiotic minocycline, known for its ability to inhibit microglia and macrophages, has been shown to be neuroprotective and reduce neuropathic pain in rat and mouse models of SCI (56;162;167).”
• Glia and pain: Is chronic pain a gliopathy? (2013, background): “IBA1 is probably the most widely used marker for microglial reaction in the pain field, partly because the IBA1 antibody from Wako Chemicals works better than other antibodies of microglial markers.”
• Minocycline: far beyond an antibiotic (2013, background): “…minocycline can exert anti-nociceptive effects on experimental neuropathic pain induced by peripheral nerve injury, inflammation or SCI, after both systemic (i.p.) and local (intrathecal) administration (Raghavendra et al., 2003; Hains and Waxman, 2006; Owolabi and Saab, 2006; Mika et al., 2007).”
• The Biology of Regeneration Failure and Success After Spinal Cord Injury. (2018, background): “However, well after maturation of the glial scar, low-level microglial activation chronically persists in the brain to affect cognitive function (417) as well as in deafferented areas rostral and caudal to the lesion where it may be involved with upregulation of extracellular matrix (ECM) components”
• MAP kinase and pain (2008, background): “Moreover, intrathecal infusion of p38 inhibitors attenuates neuropathic pain in different animal models (Jin et al., 2003; Milligan et al., 2003; Schafers et al., 2003; Tsuda et al., 2004; Hains and Waxman, 2006).”
• Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness (2016, background): “Chronic inflammatory states are associated with a hypertrophic branch morphology with an enlarged soma (Loane et al. 2014; Hains and Waxman 2006; Stalder et al. 1999).”