Trends in Neurosciences
Volume 28, Issue 2, February 2005, Pages 101-107
Journal home page for Trends in Neurosciences

Neuropathic pain and spinal microglia: a big problem from molecules in ‘small’ glia

https://doi.org/10.1016/j.tins.2004.12.002Get rights and content

Neuropathic pain is a common and severely disabling state that affects millions of people worldwide. Such pain can be experienced after nerve injury or as part of diseases that affect peripheral nerve function, such as diabetes and AIDS; it can also be a component of pain in other conditions, such as cancer. Following peripheral nerve injury, microglia in the spinal cord become activated. Recent evidence indicates that activated microglia are key cellular intermediaries in the pathogenesis of nerve injury-induced pain hypersensitivity because P2X4 purinoceptors and p38 mitogen-activated protein kinase, which are present in activated microglia, are required molecular mediators. It is important to establish how these molecules are activated in spinal microglia following nerve injury and how they cause signaling to neurons in the dorsal horn pain transmission network. Answers to these questions could lead to new strategies that assist in the diagnosis and management of neuropathic pain – strategies not previously anticipated by a neuron-centric view of pain plasticity in the dorsal horn.

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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