Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway

Abstract

Although pain is regarded traditionally as neuronally mediated, recent progress shows an important role of spinal glial cells in persistent pain sensitization. Mounting evidence has implicated spinal microglia in the development of chronic pain (e.g. neuropathic pain after peripheral nerve injury). Less is known about the role of astrocytes in pain regulation. However, astrocytes have very close contact with synapses and maintain homeostasis in the extracellular environment. In this review, we provide evidence to support a role of spinal astrocytes in maintaining chronic pain. In particular, cJun N-terminal kinase (JNK) is activated persistently in spinal astrocytes in a neuropathic pain condition produced by spinal nerve ligation. This activation is required for the maintenance of neuropathic pain because spinal infusion of JNK inhibitors can reverse mechanical allodynia, a major symptom of neuropathic pain. Further study reveals that JNK is activated strongly in astrocytes by basic fibroblast growth factor (bFGF), an astroglial activator. Intrathecal infusion of bFGF also produces persistent mechanical allodynia. After peripheral nerve injury, bFGF might be produced by primary sensory neurons and spinal astrocytes because nerve injury produces robust bFGF upregulation in both cell types. Therefore, the bFGF/JNK pathway is an important signalling pathway in spinal astrocytes for chronic pain sensitization. Investigation of signaling mechanisms in spinal astrocytes will identify new molecular targets for the management of chronic pain.

Spinal sample showing p-JNK and P38 associated with the pain signaling transduction of glial cell in neuropathic pain

“…Zhuang et al 15 found that p-JNK mediated the activation of astrocytes in spinal cord, leading to persistent neuropathic pain. Ji et al 14 described that in preserving nerve injury models, double immunofluorescencelabeling p-JNK and GFAP in the spinal dorsal horn showed their consistent distribution area. 16 In this study, in the condition that astrocytes were activated in CCI group, immunofluorescence staining of p-JNK alone, and then double immunofluorescent-labeling p-JNK with NeuN, GFAP or OX-42 were performed.…”

Cell Cycle Activation Contributes to Increased Neuronal Activity in the Posterior Thalamic Nucleus and Associated Chronic Hyperesthesia after Rat Spinal Cord Contusion

“…Microglial activation also contributes to the development and maintenance phases of chronic below-level pain after SCI [28,65,66]. To determine if the observed attenuation of below-level mechanical allodynia in CR8-treated rats may be related to the reduced activation of spinal microglial, spinal cord lumbar sections from injured rats perfused at 5 weeks after SCI were stained for ED1/Iba-1, and activated microglia within the superficial dorsal horn were quantified.…”

Do glial cells control pain?

“…The emergence of glial cells as important players in pain control and also as new targets for pain medicine has brought great excitement to the pain research field. We have discussed the role of astrocytes in the previous review (Ji et al, 2006) and the role of microglia in the current review. In the normal conditions, there seems to be limited role of glia, as none of the treatments cited above really changes the baseline pain thresholds in animals.…”

“…Both microglia and astrocytes are activated in these pain models and interact with neurons in the complex pain pathophysiology. We have recently discussed the role of astrocytes in pain control in this journal (Ji et al, 2006). In this review, we will focus on how activation of microglia controls abnormal pain.…”