Abstract
BackgroundThere is accumulating evidence that the activation of spinal glial cells, especially microglia, is a key event in the pathogenesis of neuropathic pain. However, the inhibition of microglial activation is often ineffective, especially for long-lasting persistent neuropathic pain. So far, neuropathic pain remains largely intractable and a new therapeutic strategy for the pain is still required.Methods/Principal FindingsUsing Seltzer model mice, we investigated the temporal aspect of two types of neuropathic pain behaviors, i.e., thermal hyperalgesia and mechanical allodynia, as well as that of morphological changes in spinal microglia and astrocytes by immunohistochemical studies. Firstly, we analyzed the pattern of progression in the pain behaviors, and found that the pain consisted of an “early induction phase” and subsequent “late maintenance phase”. We next analyzed the temporal changes in spinal glial cells, and found that the induction and the maintenance phase of pain were associated with the activation of microglia and astrocytes, respectively. When Bushi, a Japanese herbal medicine often used for several types of persistent pain, was administered chronically, it inhibited the maintenance phase of pain without affecting the induction phase, which was in accordance with the inhibition of astrocytic activation in the spinal cord. These analgesic effects and the inhibition of astrocytic activation by Bushi were mimicked by the intrathecal injection of fluorocitrate, an inhibitor of astrocytic activation. Finally, we tested the direct effect of Bushi on astrocytic activation, and found that Bushi suppressed the IL-1β- or IL-18-evoked ERK1/2-phosphorylation in cultured astrocytes but not the ATP-evoked p38- and ERK1/2-phosphorylation in microglia in vitro.ConclusionsOur results indicated that the activation of spinal astrocytes was responsible for the late maintenance phase of neuropathic pain in the Seltzer model mice and, therefore, the inhibition of astrocytic activation by Bushi could be a useful therapeutic strategy for treating neuropathic pain.
Highlights
Neuropathic pain is the chronic pain state after a lesion or disease of the peripheral or central nervous system such as bone compression in cancer, diabetes, infection and acquired immunodeficiency syndrome [1]
Our results indicated that the activation of spinal astrocytes was responsible for the late maintenance phase of neuropathic pain in the Seltzer model mice and, the inhibition of astrocytic activation by Bushi could be a useful therapeutic strategy for treating neuropathic pain
We show that neuropathic pain consists of the microglia-mediated early induction phase and the subsequent astrocyte-mediated maintenance phase in Seltzer model mice, and demonstrate that Bushi exerts its analgesic effect against the maintenance phase of neuropathic pain by inhibiting the activation of astrocytes but not microglia
Summary
Neuropathic pain is the chronic pain state after a lesion or disease of the peripheral or central nervous system such as bone compression in cancer, diabetes, infection and acquired immunodeficiency syndrome [1]. Neuropathic pain has long been considered to be caused by relevant changes in neurons, emerging lines of evidence have revealed that morphological and functional changes occur in spinal glial cells [6,7,8], especially in microglia, the immune cells in the CNS [2,3,9,10,11,12]. Microglia change their shapes and characteristic features from ‘resting’ to ‘activated’ through a series of cellular and molecular changes. Such activated microglia produce several diffusible molecules such as BDNF, by which microglia alter the excitability of adjacent neurons in the dorsal horn, leading to tactile allodynia [13]. Neuropathic pain remains largely intractable and a new therapeutic strategy for the pain is still required
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