The neuropathic pain triad: Neurons, immune cells, and glia

Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Nature Neuroscience (Impact Factor: 14.98). 12/2007; 10(11):1361-8. DOI: 10.1038/nn1992
Source: PubMed

ABSTRACT Nociceptive pain results from the detection of intense or noxious stimuli by specialized high-threshold sensory neurons (nociceptors), a transfer of action potentials to the spinal cord, and onward transmission of the warning signal to the brain. In contrast, clinical pain such as pain after nerve injury (neuropathic pain) is characterized by pain in the absence of a stimulus and reduced nociceptive thresholds so that normally innocuous stimuli produce pain. The development of neuropathic pain involves not only neuronal pathways, but also Schwann cells, satellite cells in the dorsal root ganglia, components of the peripheral immune system, spinal microglia and astrocytes. As we increasingly appreciate that neuropathic pain has many features of a neuroimmune disorder, immunosuppression and blockade of the reciprocal signaling pathways between neuronal and non-neuronal cells offer new opportunities for disease modification and more successful management of pain.

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Available from: Clifford J Woolf, Aug 30, 2015
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    • "Peripheral nerves are the source of almost all forms of neuropathic pain. Neuropathic pain is a complex syndrome resulting from many different forms of peripheral nerve damage, such as traumatic nerve damage, diabetes, and infections, as well as immune system and metabolic diseases [6]. For decades, a neuron-centered argument has been frequently used to explain the pathophysiology of chronic pain; however, recent studies have shifted attention towards a neuroimmune interaction. "
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    • "mechanisms. These neuronal pathophysiological mechanisms are being supplemented by an appreciation for the role of central immune signaling, such that neuropathic pain, for instance, is now considered as a neuroimmune disorder [3] (Fig. 1). "
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    ABSTRACT: Chronic pain is a debilitating condition and, in most cases, difficult to treat. A prominent example of this is neuropathic pain. Understanding pathophysiological mechanisms of pain and, therefore, make this knowledge into an effective treatment is still a challenge to experts. Pain can now be considered a neuro-immune disorder, since recent data indicates critical involvement of innate and adaptive immune responses following injury, and this interaction plays an important role in the onset and perpetuation of chronic pain. The aim of this article is to review the relationship between immune system and chronic pain, especially about neuropathic pain, and focusing on cytokines, chemokines and lymphocytes.
    Inflammation & Allergy - Drug Targets (Formerly ?Current Drug Targets - Inflammation & Allergy) 01/2015; 13(5). DOI:10.2174/1871528114666150114170004
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    • "Chronic pain that resulted from inflammation, infection, nerve injury , or cancer is a major public health problem worldwide. Neuroinflammation , which is mediated by a variety of inflammatory mediators, including cytokines and chemokines, has been recently recognized to play an important role in the pathogenesis of chronic pain (Mennicken et al., 1999; Miller et al., 2008; Scholz and Woolf, 2007; White et al., 2007). Chemokines are a family of small (8–12 kDa) proteins involved in the modulation of numerous biological functions, including leukocyte migration and activation, cell adhesion, and T cell activation via Gprotein-coupled receptors (GPCR). "
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    ABSTRACT: Recent studies have shown that CXCL1 upregulation in spinal astrocytes is involved in the maintenance of neuropathic pain. However, whether and how CXCL1 regulates inflammatory pain remains unknown. Here we show that intraplantar injection of CFA increased mRNA and protein expressions of CXCL1 and its major receptor CXCR2 in the spinal cord at 6 hours and 3 days after the injection. Immunofluorescence double staining showed that CXCL1 and CXCR2 were expressed in spinal astrocytes and neurons, respectively. Intrathecal injection of CXCL1 neutralizing antibody or CXCR2 antagonist SB225002 attenuated CFA-induced mechanical and heat hypersensitivity on post-CFA day 3. Patch-clamp recordings showed that CXCL1 potentiated NMDA-induced currents in lamina II neurons via CXCR2, and this potentiation was further increased in CFA-treated mice. Furthermore, intrathecal injection of CXCL1 increased COX-2 expression in dorsal horn neurons, which was blocked by pretreatment with SB225002 or MEK (ERK kinase) inhibitor PD98059. Finally, pretreatment with SB225002 or PD98059 decreased CFA-induced heat hyperalgesia and COX-2 mRNA/protein expression and ERK activation in the spinal cord. Taken together, our data suggest that CXCL1, upregulated and released by spinal astrocytes after inflammation, acts on CXCR2-expressing spinal neurons to increase ERK activation, synaptic transmission and COX-2 expression in dorsal horn neurons and contributes to the pathogenesis of inflammatory pain.
    Experimental Neurology 11/2014; 261. DOI:10.1016/j.expneurol.2014.05.014 · 4.62 Impact Factor
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