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.

The blockade of CC chemokine receptor type 1 influences the level of nociceptive factors and enhances opioid analgesic potency in a rat model of neuropathic pain

“…It is well known that glial cells are involved in pain development . There are many reports showing the morphological changes of activated microglia/macrophages after nerve injury in immunofluorescence studies . We observed, using Western blot analysis, a strong increase in the number of IBA‐1‐positive cells on the 7th day post‐CCI in the spinal cord and the DRG, which is in agreement with other data .…”

Microglia control the spread of neurotropic virus infection via P2Y12 signalling and recruit monocytes through P2Y12-independent mechanisms

“…Microglia are capable of removing synapses via complement-mediated manner [26,59] and eliminate injured neurons via recognising translocated phosphatidylserine on the cell membrane [7]. Numerous mediators including chemokines, metalloproteinases, growth factors, purinergic metabolites, alarmins or damageassociated molecular patterns such as HMGB1, histones and DNA have been revealed as indicators of neuronal injury and triggers for microglial activation [9,29,30,57,58]. Among these, microglial P2Y12 receptor-mediated actions have been shown to facilitate the movement of microglial processes to sites of injury or ATP administration [14,25], whilst constant microglial surveillance of the brain was found to be largely P2Y12-independent [39,53].…”

The neuroprotective effects of micronized PEA (PEA‐m) formulation on diabetic peripheral neuropathy in mice

“…Spinal microglia are crucial for diabetic neuropathic pain. Activated microglia show dramatic changes in the expression of various genes, including cell surface receptors for neurotransmission, intracellular signaling molecules (such as MAPKs), proinflammatory cytokines, and neurotrophic factors (14).…”