Glial Cells and Chronic Pain

Pain Research Unit, Department of Anesthesiology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.
The Neuroscientist (Impact Factor: 6.84). 10/2010; 16(5):519-31. DOI: 10.1177/1073858409360822
Source: PubMed


Over the past few years, the control of pain exerted by glial cells has emerged as a promising target against pathological pain. Indeed, changes in glial phenotypes have been reported throughout the entire nociceptive pathway, from peripheral nerves to higher integrative brain regions, and pharmacological inhibition of such glial reactions reduces the manifestation of pain in animal models. This complex interplay between glia and neurons relies on various mechanisms depending both on glial cell types considered (astrocytes, microglia, satellite cells, or Schwann cells), the anatomical location of the regulatory process (peripheral nerve, spinal cord, or brain), and the nature of the chronic pain paradigm. Intracellularly, recent advances have pointed to the activation of specific cascades, such as mitogen-associated protein kinases (MAPKs) in the underlying processes behind glial activation. In addition, given the large number of functions accomplished by glial cells, various mechanisms might sensitize nociceptive neurons including a release of pronociceptive cytokines and neurotrophins or changes in neurotransmitter-scavenging capacity. The authors review the conceptual advances made in the recent years about the implication of central and peripheral glia in animal models of chronic pain and discuss the possibility to translate it into human therapies in the future.

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Available from: Ru-Rong Ji,
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    • "The pronociceptive role of ATP in nociception is well characterized [3-8]. This effect has been associated with the activation of the P2X family receptors expressed in dorsal root ganglion [9-12], satellite glial cells [13,14], spinal dorsal horn [15-17] and microglia/astrocytes [16,18,19]. Following nerve damage, spinal microglia and astrocytes proliferate and up-regulate specific protein markers like ionized calcium-binding adapter molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP), respectively [20,21]. "
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    ABSTRACT: Background The participation of spinal P2X receptors in neuropathic pain is well recognized. However, the role of P2Y receptors has been less studied. The purpose of this study was to investigate the contribution of spinal P2Y6,11 receptors following peripheral nerve damage induced by spinal nerve ligation. In addition, we determined the expression of P2Y6,11 receptors in the dorsal spinal cord in presence of the selective P2Y6,11 receptors antagonists. Furthermore, we evaluated the participation of spinal microglia and astrocytes in the pronociceptive role of P2Y6,11 receptors. Results Spinal administration of the selective P2Y6 (MRS2578, 10–100 μM) and P2Y11 (NF340, 0.3–30 μM) receptor antagonists reduced tactile allodynia in spinal nerve ligated rats. Nerve injury increased the expression of P2Y6,11 receptors at 7, 14 and 21 days after injury. Furthermore, intrathecal administration of MRS2578 (100 μM/day) and NF340 (30 μM/day) for 3 days significantly reduced spinal nerve injury-induced increase in P2Y6,11 receptors expression, respectively. Spinal treatment (on day 14 after injury) with minocycline (100 μg/day) or fluorocitrate (1 nmol/day) for 7 days reduced tactile allodynia and spinal nerve injury-induced up-regulation in Iba-1 and GFAP, respectively. In addition, minocycline reduced nerve injury-induced up-regulation in P2Y6,11 receptors whereas that fluorocitrate diminished P2Y11, but not P2Y6, receptors up-regulation. Intrathecal treatment (on day 21 after injury) with the selective P2Y6 (PSB0474, 3–30 μM) and P2Y11 (NF546, 1–10 μM) receptor agonists produced remarkable tactile allodynia in nerve ligated rats previously treated with minocycline or fluorocitrate for 7 days. Conclusions Our data suggest that spinal P2Y6 is present in spinal microglia while P2Y11 receptors are present in both spinal microglia and astrocytes, and both receptors are up-regulated in rats subjected to spinal nerve injury. In addition, our data suggest that the spinal P2Y6 and P2Y11 receptors participate in the maintenance of neuropathic pain.
    Molecular Pain 05/2014; 10(1):29. DOI:10.1186/1744-8069-10-29 · 3.65 Impact Factor
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    • "Other presumptions made by the Gate Control Theory, such as spinal dorsal horn termination of primary afferents, have not been borne out by experimental data. In addition, the theory did not foresee a role of glial cells, which vastly outnumber neurons, in modulating pain perception and there is no accounting for potential plasticity of the nervous system following injury or disease [3]. Even after acknowledging flaws of the Gate Control Theory, it is still characterized as having led to " significant advancement " of our understanding of pain [1]. "
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    ABSTRACT: Neuropathic pain is a chronic disability associated with a dysfunction of the nervous system, initiated by a primary lesion or disease. Even after resolution of the initiating pathology, neuropathic pain often persists, leading to a significantly diminished quality of life. A vast literature has documented alterations in the expression and distribution of various pain-related proteins in the peripheral nervous system following injury or disease. The current review examines pain-related molecules in the pathogenesis of peripheral nerve injury-induced pain and discusses potentially useful therapeutic targets on the basis of preclinical findings in rodent neuropathic pain models. There are indeed a number of cellular processes that are involved in maintaining the neuropathic pain state, but the current review will focus on transmembrane proteins, particularly the voltage-gated and ligand-gated ion channels, which modulate peripheral nerve function. Given the complexity of the process involved in peripheral nerves, clinical efficacy could be greatly enhanced if several of these targets are engaged at once. A key advantage of therapy directed peripherally is that penetration of the therapeutic into the CNS is not entirely necessary, thereby reducing the risk of adverse psychomotor effects. While a number of fascinating targets have been identified in preclinical rodent models, there is a need to confirm that they are in fact relevant to clinical neuropathic pain. Thus, the current review will also discuss the extent to which clinical data confirms the findings of preclinical studies.
    CNS & neurological disorders drug targets 05/2014; DOI:10.2174/1871527313666140711092415 · 2.63 Impact Factor
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    • "Much like activated microglia, activated astrocytes promote (dorsal horn) neuron dysfunction by releasing BDNF (Ren and Dubner, 2010), IL-1β, IL-6 and TNFα (Beurel et al., 2010). However, because their activation is more prolonged than that of microglia, astrocytes are required to perpetuate the neuronal hyperexcitability, neurotoxicity and inflammation that characterizes neuropathic pain (Ji and Suter, 2007; Gosselin et al., 2010; Zhuo et al., 2011). "
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    ABSTRACT: Peripheral neuropathy is a widespread and potentially incapacitating pathological condition that encompasses more than 100 different forms and manifestations of nerve damage. The diverse pathogenesis of peripheral neuropathy affects autonomic, motor and/or sensory neurons, and the symptoms that typify the condition are abnormal cutaneous sensation, muscle dysfunction and, most notably, chronic pain. Chronic neuropathic pain is difficult to treat and is often characterized by either exaggerated responses to painful stimuli (hyperalgesia) or pain resulting from stimuli that would not normally provoke pain (allodynia). The objective of this review is to provide an overview of some pathways associated with the development of peripheral neuropathy and then discuss the benefits of exercise interventions. The development of neuropathic pain is a highly complex and multifactorial process, but recent evidence indicates that the activation of spinal glial cells via the enzyme glycogen synthase kinase 3 and increases in the production of both pro-inflammatory cytokines and brain derived neurotropic factor are crucial steps. Since many of the most common causes of peripheral neuropathy cannot be fully treated, it is critical to understand that routine exercise may not only help prevent some of those causes, but that it has also proven to be an effective means of alleviating some of the condition's most distressing symptoms. More research is required to elucidate the typical mechanisms of injury associated with peripheral neuropathy and the exercise-induced benefits to those mechanisms.
    Frontiers in Cellular Neuroscience 04/2014; 8(1):102. DOI:10.3389/fncel.2014.00102 · 4.29 Impact Factor
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