Microglia in the spinal cord and neuropathic pain

Abstract

In contrast to physiological pain, pathological pain is not dependent on the presence of tissue-damaging stimuli. One type of pathological pain - neuropathic pain - is often a consequence of nerve injury or of diseases such as diabetes. Neuropathic pain can be agonizing, can persist over long periods and is often resistant to known painkillers. A growing body of evidence shows that many pathological processes within the central nervous system are mediated by complex interactions between neurons and glial cells. In the case of painful peripheral neuropathy, spinal microglia react and undergo a series of changes that directly influence the establishment of neuropathic pain states. After nerve damage, purinergic P2X4 receptors (non-selective cation channels activated by extracellular adenosine triphosphate) are upregulated in spinal microglia in a manner that depends on the transcription factors interferon regulatory factor 8 and 5, both of which are expressed in microglia after peripheral nerve injury. P2X4 receptor expression on the cell surface of microglia is also regulated at the post-translational level by signaling from CC chemokine receptor chemotactic cytokine receptor 2. Furthermore, spinal microglia in response to extracellular stimuli results in signal transduction through intracellular signaling cascades, such as mitogen-activated protein kinases, p38 and extracellular signal-regulated protein kinase. Importantly, inhibiting the function or expression of these microglial molecules suppresses the aberrant excitability of dorsal horn neurons and neuropathic pain. These findings show that spinal microglia are a central player in mechanisms for neuropathic pain, and might be a potential target for treating the chronic pain state.

Keywords: Microglia; Painful diabetic neuropathy; Purinergic receptors.

Figure 1

Schematic illustration of primary afferent sensory fibers and neuronal circuits in the dorsal horn. The dorsal root ganglion contains cell bodies of primary afferent neurons that transmit sensory information from the periphery to the spinal dorsal horn. Nociceptive information is mainly mediated by Aδ and C fibers, and innocuous mechanical information is mediated by Aβ fibers. C and Aδ fibers terminate in the superficial dorsal horn, and activate projection neurons and excitatory interneurons. The terminals of Aβ fibers are concentrated in the deeper dorsal horn, and connect to excitatory and inhibitory interneurons.

Figure 2

Activation of microglia in the dorsal horn of the spinal cord after peripheral nerve injury. (a) Immunofluorescence of the microglia marker ionized calcium‐binding adapter molecule‐1 in the spinal dorsal horn 7 days after nerve injury. High‐magnified images of (b) normal and (c) activated states of microglia in the contralateral and ipsilateral side, respectively, of the spinal dorsal horn.

Figure 3

Schematic illustration for shifting spinal microglia toward a P2X4 receptor (P2XR4)‐expressing reactive state through an interferon regulatory factor 8 (IRF8)–IRF5 transcriptional axis after nerve injury, and a potential mechanism by which P2X4⁺ microglia cause hyperexcitability in dorsal horn neurons and neuropathic pain. After nerve injury, activated microglia show increased expression of IRF8, which in turn leads to induction of IRF5 expression. IRF5 then induces P2X4R expression by directly binding to the promoter region of the P2rx4 gene. P2X4R is activated by extracellular adenosine triphosphate (ATP; which could be presumably released from neurons or glial cells) and, in turn, release bioactive diffusible factors, such as brain‐derived neurotrophic factor (BDNF). BDNF downregulates the potassium‐chloride transporter, KCC2, through tropomyosin‐related kinase B, causes an increase in intracellular [Cl⁻], and leads to the collapse of the transmembrane anion gradient in dorsal horn neurons, which in turn induces depolarization of these neurons after stimulation by γ‐aminobutyric acid and glycine (which might be released in response to stimulation of Aβ fiber). The resultant hyperexcitability in the dorsal horn pain network induced by microglial factors could be responsible for neuropathic pain. GABA, γ‐aminobutyric acid.