Trends in Neurosciences
Neuropathic pain and spinal microglia: a big problem from molecules in ‘small’ glia
Section snippets
Microglia activation after PNI
Microglia represent 5–10% of glia in the CNS and are often considered resident macrophages 8, 9, 10. In adults, microglia are distributed throughout CNS and, unlike macrophages, have a small soma bearing thin and branched processes under normal conditions. Such microglia are said to be ‘resting’, but resting microglia are not dormant: rather, they act as sensors for a range of stimuli that threaten physiological homeostasis, including CNS trauma, ischemia and infection. Once activated by one or
The P2X4 receptor and p38 MAPK in spinal microglia are intermediaries in nerve injury-induced pain hypersensitivity
There is abundant evidence that microglia are activated in the dorsal horn in a wide variety of nerve injury models 5, 6, 7, 21, 22, 23, 24, 26, but until recently it remained an open question whether spinal microglia have a causal role in nerve injury-evoked pain behaviors. However, several studies have implicated activated microglia in the pathogenesis of pain hypersensitivity by demonstrating that the enhancement of pain behaviors after nerve injury requires the P2X4 receptor [38] and p38
Other molecules expressed in spinal microglia that might contribute to nerve injury-induced pain behaviors
Chemotactic cytokine receptor 2 (CCR2), which is a receptor for monocyte chemoattractant protein-1 (MCP-1) [46], is upregulated in spinal microglia after nerve injury [47]. Mutant mice lacking CCR2 (CCR2−/−) do not display tactile allodynia after nerve injury [47], providing genetic evidence that CCR2 is necessary for PNI-induced tactile allodynia. However, whether CCR2 within spinal microglia is responsible is unclear because CCR2 is also upregulated in the peripheral nerve, at the site of the
Framework for investigating modulation of dorsal horn pain signaling by activated microglia
Given the evidence that molecules expressed in activated spinal microglia following PNI – P2X4 receptors and p38MAPK – are necessary for producing pain hypersensitivity, a major issue is determining the mechanism(s) by which microglia promote pain hypersensitivity. Clearly, this must involve effects of the microglia on neurons in the pain-processing network within the dorsal horn, but how? There are several general possibilities to consider. Based on the immunological functions of microglia,
Is there a distinctive activation or signaling state of microglia after PNI?
Activation of microglia by CNS infection or injury is not a unitary process, and various microglial proteins are altered in different time courses and amounts, depending on which stimulus produces the activation 8, 9, 10, 12, 64. This leads to functional and phenotypic heterogeneity in activation of microglia under a variety of CNS conditions 12, 64. There is evidence of heterogeneity in the responses of spinal microglia to peripheral stimulation, and this heterogeneity might depend on the type
Potential clinical implications for neuropathic pain and other CNS disorders
Almost all drugs currently used for neuropathic pain were developed, or are considered to act, against molecular targets in neurons, and none of these drugs exhibits optimal therapeutic effects in patients [7]. The findings described here suggest that targeting those molecular processes in microglia that mediate PNI-induced pain hypersensitivity could be an alternative for developing pharmacological agents to treat neuropathic pain. The molecules that mediate microglial activation following
Concluding remarks
As has been reviewed here, PNI leads to changes in the spinal cord that cause functional and phenotypic alterations in microglia. It is hypothesized that activated molecular pathways lead to signaling from microglia to neurons within the dorsal horn and ultimately change the properties of the spinal pain-processing network to bring about PNI-induced pain hypersensitivity. How these molecular pathways become activated in spinal microglia when a nerve is damaged in the periphery, and what effects
Acknowledgements
We thank J. Hicks for corrections of the manuscript. This work was supported partly by a grant from the Organization for Pharmaceutical Safety and Research, by a grant-in-aid for the scientific research from the Ministry of Education, Science, Sports, and Culture of Japan, by a grant from the Japan Health Sciences Foundation and by a grant from the Japan Society for the Promotion of Science (JSPS) and Canadian Institutes of Health Research (CIHR) Joint Health Research Program Project. M.T. is a
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