Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential

Abstract

Acute nociceptive pain is a key defence system that enables the detection of danger signals that threaten homeostasis and survival. However, chronic pain (such as the neuropathic pain that occurs after peripheral nerve injury) is not simply a consequence of the continuity of acute nociceptive signals but rather of maladaptive nervous system function. Over recent decades, studies have provided evidence for the necessity and sufficiency of microglia for the alterations in synaptic remodelling, connectivity and network function that underlie chronic pain and have shed light on the underlying molecular and cellular mechanisms. It is also becoming clear that microglia have active roles in brain regions important for the emotional and memory-related aspects of chronic pain. Recent advances in the development of new drugs targeting microglia and the establishment of new sources of human microglia-like cells may facilitate translation of these findings from bench to bedside.

Temporal Kinetics of Microgliosis in the Spinal Dorsal Horn after Peripheral Nerve Injury in Rodents

“…4) The time course of the PNIinduced SDH microgliosis in mice was revealed to be that microglia number increased from day 3, peaked at 1 week and declined later, which is almost similar to the temporal pattern of microgliosis reported in previous studies. 11,25,26) Under such conditions, we clearly showed that a proliferation burst of SDH microglia occurred during the early phase (the first 3 d after PNI) but not during the later phase (at least until 2 weeks post-PNI).…”

“…Because a recent study has demonstrated that interrupting spinal microgliosis suppresses PNI-induced mechanical pain hypersensitivity and provided evidence that it is a crucial step in neuropathic pain, 11) the kinetics of microglial proliferation after PNI would also provide valuable information for developing a new therapeutic strategy. 4) In the present study we fully characterized the kinetics of microglial proliferation in the SDH after PNI and identified for the first time an unexpected narrow time window to rapidly induce a proliferation burst of SDH microglia after PNI.…”

“…4,10,11) However, in stark contrast to the characterization of temporal and spatial changes in the immunostaining levels of microglial markers (CD11b or ionized calcium-binding adapter molecule 1 (Iba1)) in the SDH that have so far been extensively studied, 4) the temporal kinetics of microglial proliferation after PNI have yet to be fully characterized. While recent studies reported an involvement of colony-stimulating factor 1 (CSF1) expressed in injured dorsal root ganglion (DRG) neurons in the PNI-induced proliferation, 4,13,14) the expression of CSF1 in DRG neurons (and also its receptor CSF1R in microglia) is upregulated for a few weeks after PNI 13,14) when microglial proliferation has already terminated. 11,15) Thus, determining the kinetics of microglial proliferation after PNI would provide an important clue to identify a molecule(s) for the PNI-induced proliferation of SDH microglia.…”

“…Two possible mechanisms (proliferation of resident microglia 10,11) and infiltration of bone marrow-derived monocytes 12) ) have been considered, but it is now thought that local expansion of resident microglia by proliferation is the primary cellular basis for SDH microgliosis after PNI. 4,10,11) However, in stark contrast to the characterization of temporal and spatial changes in the immunostaining levels of microglial markers (CD11b or ionized calcium-binding adapter molecule 1 (Iba1)) in the SDH that have so far been extensively studied, 4) the temporal kinetics of microglial proliferation after PNI have yet to be fully characterized. While recent studies reported an involvement of colony-stimulating factor 1 (CSF1) expressed in injured dorsal root ganglion (DRG) neurons in the PNI-induced proliferation, 4,13,14) the expression of CSF1 in DRG neurons (and also its receptor CSF1R in microglia) is upregulated for a few weeks after PNI 13,14) when microglial proliferation has already terminated.…”

“…Following PNI, SDH microglia become activated through a progressive series of changes in their morphology, expression of a variety of genes and cell number. 4) One of the most prominent features of microglial activation is an increase in the number of microglia (called microgliosis). Since PNI-induced microgliosis in the SDH was recorded in 1970s 5) and the rodent models of neuropathic pain were established in 1990s, [6][7][8][9] studies have investigated the mechanism for microgliosis in the SDH after PNI.…”