Hiraga et al.

Inflammation and Regeneration (2022) 42:15

https://doi.org/10.1186/s41232-022-00199-6
Inflammation and Regeneration

REVIEW Open Access

Neuroplasticity related to chronic pain and

its modulation by microglia
Shin-ichiro Hiraga1,2, Takahide Itokazu1,2*, Mariko Nishibe3 and Toshihide Yamashita1,2,4,5*

Abstract
Neuropathic pain is often chronic and can persist after overt tissue damage heals, suggesting that its underlying
mechanism involves the alteration of neuronal function. Such an alteration can be a direct consequence of nerve
damage or a result of neuroplasticity secondary to the damage to tissues or to neurons. Recent studies have shown
that neuroplasticity is linked to causing neuropathic pain in response to nerve damage, which may occur adjacent
to or remotely from the site of injury. Furthermore, studies have revealed that neuroplasticity relevant to chronic
pain is modulated by microglia, resident immune cells of the central nervous system (CNS). Microglia may directly
contribute to synaptic remodeling and altering pain circuits, or indirectly contribute to neuroplasticity through
property changes, including the secretion of growth factors. We herein highlight the mechanisms underlying
neuroplasticity that occur in the somatosensory circuit of the spinal dorsal horn, thalamus, and cortex associated
with chronic pain following injury to the peripheral nervous system (PNS) or CNS. We also discuss the dynamic
functions of microglia in shaping neuroplasticity related to chronic pain. We suggest further understanding of post-
injury ectopic plasticity in the somatosensory circuits may shed light on the differential mechanisms underlying
nociceptive, neuropathic, and nociplastic-type pain. While one of the prominent roles played by microglia appears
to be the modulation of post-injury neuroplasticity. Therefore, future molecular- or genetics-based studies that
address microglia-mediated post-injury neuroplasticity may contribute to the development of novel therapies for
chronic pain.
Keywords: Nociplastic pain, Neuroplasticity, Microglia, PNS injury, CNS injury, Thalamic hemorrhage

Introduction a third type of pain, apart from the two pain mecha-
Injuries to neural circuits, whether in the peripheral or nisms, which are nociceptive pain (caused by tissue dam-
central somatosensory system, can result in neuropathic age or threaten tissue damage) and neuropathic pain
pain, an intractable chronic pain manifests as an array of (caused by damage to the peripheral nervous system
symptoms and signs [1]. The prevalence of chronic pain [PNS] or central nervous system [CNS]). Although noci-
increases with age, and pain is associated with decreased plastic pain can manifest solely, the symptoms often
quality of life, opioid dependence, and poor mental occur as part of a mixed state with the other two mecha-
health. The International Association for the Study of nisms [2]. To regulate pain occurrence, it is important
Pain has recently proposed a new mechanism of pain de- to understand whether the pathophysiology of pain is a
velopment termed nociplastic pain, a type of pain that direct result of nervous system trauma or a result of
occurs as a result of plastic changes in the neural circuits neuroplastic changes secondary to trauma to tissues or
carrying nociceptive information [2]. Nociplastic pain is to neurons. Recently, microglia, the resident immune
cells of the CNS, have emerged as a key modulator of
* Correspondence: t.itokazu@molneu.med.osaka-u.ac.jp; neurons in regulating synaptic pruning, formation, and
yamashita@molneu.med.osaka-u.ac.jp transmission, thereby contributing to the pathophysi-
1
Department of Neuro-Medical Science, Graduate School of Medicine, Osaka
University, Suita, Osaka, Japan
ology of pain [3]. The role of microglia in the spinal dor-
Full list of author information is available at the end of the article sal horn in modulating neuropathic pain has been well
© The Author(s). 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
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Hiraga et al. Inflammation and Regeneration (2022) 42:15 Page 2 of 10

studied compared to the role of intracerebral microglia complete Freund’s adjuvant (CFA)-elicited inflammatory
[4]. We reported the involvement of intracerebral micro- injury. Commonly affected by both neuropathic and in-
glia in the development of chronic pain associated with flammatory injuries, a subset of CCK neurons composed
the alteration of nociceptive neural circuitry post-CNS of transient vesicular glutamate transporter 3
injury [5]. In this review, we highlight the neuroplastic (tVGLUT3) neuron, is involved in developing dynamic
mechanisms that occur in somatosensory circuits in the mechanical allodynia, making synaptic connections with
spinal dorsal horn, thalamus, or cortex associated with PKCγ neurons. This VGLUT3/CCK/PKCγ circuit ultim-
chronic pain, following injury to the PNS or CNS. We ately sends the input to the projection neurons in lamina
then discuss the dynamic functions of microglia in shap- I through vertical cells [16].
ing neuroplasticity related to chronic pain. Another well-studied neuroplastic change associated
with allodynia occurs in neuropeptide Y promoter (Npy)
Neuroplasticity of spinal dorsal horn interneurons inhibitory interneurons [19]. The Npy inhibitory inter-
in chronic pain following a PNS injury neurons in the outer lamina II (IIo) send inhibitory
The dorsal horn of the spinal cord, organized into six gamma-aminobutyric acid (GABA) signals to projection
Rexed laminae and composed broadly of excitatory and neurons in lamina I. The excitability of Npy neurons de-
inhibitory neurons, gathers sensory information of the creased after a PNS injury, inducing touch-evoked pain-
peripheral tissues through the afferent sensory neurons. like behavior, which improved by increasing the excit-
Nociceptive information is transmitted to the superficial ability of the interneurons. Notably, the axons of Npy
laminae I and II of the dorsal horn, and non-nociceptive neurons project to lamina III/IV cells, including PKCγ
information is transmitted to the deep laminae II–VI. neurons [20], the subtype of interneurons that is closely
Integrated sensory information is then relayed to several associated with noxious stimuli. Our research group has
brain regions, including the thalamus. When a periph- identified that Netrin-4, a laminin-related extracellular
eral injury occurs to an extent that alters the somatosen- protein, was expressed exclusively in the excitatory inter-
sory information processing system, it often leads to neurons of the lamina IIi, mediating tactile and heat
evoking pain sensation by normally non-noxious stimuli. hyperalgesia following a PNS injury [8]. Neurophysio-
Such an alteration in pain perception is often induced by logical experiments showed that Netrin-4 neurons in-
structural and functional neuroplasticity of the spinal duced pain sensation through an increase in the
dorsal horn due to its closely related anatomical struc- excitatory transmission of N-methyl-D-aspartic acid
tures of each lamina. Pain evoked by non-noxious stim- (NMDA) receptors. Together, synaptic modifications in
uli is called allodynia and it is one of the characteristics the dorsal horn circuits of the spinal cord result in a bal-
of neuropathic and nociplastic pain. ance alteration of synaptic transmission of excitation
The excitatory and inhibitory neurons in the spinal and inhibition in lamina I projection neurons to the
dorsal horn have been morphologically and electrophysi- brain, which account at least partially for the develop-
ologically analyzed, and their subtypes have also been ment and maintenance of chronic pain.
identified by molecular and gene expression profiles [6–
11]. These findings promote the understanding of neu- Neuroplasticity of thalamocortical (somatosensory
roplasticity occurring in interneurons of the spinal dor- cortex) circuit in chronic pain after a PNS or CNS
sal horn circuit, which is associated with allodynia after injury
PNS injury. Novel pain circuits relevant to neuropathic Noxious and non-noxious stimuli applied to peripheral
and nociplastic pain are still being discovered within the tissues are conveyed to the brain via the spinal cord
dorsal horn (Fig. 1A). For instance, the gamma isoform mainly by the projection neurons in lamina I and V of
of protein kinase C (PKCγ) interneurons, defined by the the spinal dorsal horn [21]. The projection neurons in
expression of Tac2, neurotensin, and cholecystokinin lamina I transmit nociceptive information to the peria-
(CCK) [12] localized within the lamina IIiV/III border queductal gray matter (PAG), lateral parabrachial area
and partially in laminae I and deeper III, have been (LPb), and ventral posterolateral nucleus (VPL) of the
shown to mediate mechanical allodynia induced by thalamus. The majority of the projection neurons in
neuropathic injuries. These pain mediations were shown lamina V also terminate in the thalamic VPL nucleus
to be through PKCγ neurons losing at least a partial syn- and convey non-noxious stimuli. Therefore, the thalamic
aptic connection with parvalbumin or with glycine in- VPL nucleus, the “first-order nucleus,” serves as a gate-
hibitory neurons [12–17], and partially through way that processes both noxious and non-noxious stim-
interactions with 5-hydroxytryptamine receptor 2A (5- uli to the fourth layer of the primary somatosensory
HT2A) [18]. This subtype of neurons differs from calre- cortex (S1L4). The inputs from the S1 are sent to the
tinin (CR) neurons located in the inner lamina II (IIi), fourth layer of the secondary somatosensory cortex
which mediates mechanical allodynia induced by (S2L4) via the posterior nucleus (PO) of the thalamus,
Hiraga et al. Inflammation and Regeneration (2022) 42:15 Page 3 of 10

Fig. 1 (See legend on next page.)

Hiraga et al. Inflammation and Regeneration (2022) 42:15 Page 4 of 10

(See figure on previous page.)

Fig. 1 The spinal dorsal horn and S1 neuroplasticity mechanism inducing chronic pain following PNS or CNS injury. A Synaptic modifications in
the dorsal horn of the spinal cord result in a balance alteration of excitatory and inhibitory synaptic transmission in lamina I projection neurons to
the brain, which account at least partially for pain sensation evoked by non-noxious stimuli. The continuous lines and arrows indicate allodynia-
relevant circuits while dotted lines indicate neuronal activity suppression or synaptic loss in the cause of enhanced pathology. Arrowheads
indicate the direction of excitatory inputs. PV, parvalbumin-expressing neurons; SOM, somatostatin-expressing neurons; CCK, cholecystokinin-
expressing neurons; VGLUT3, vesicular glutamate transporter 3-expressing neurons; PKCγ, protein kinase C gamma-expressing neurons; CR,
calretinin-expressing neurons; Gly, glycine-expressing neurons; Netrin-4, netrin-4-expressing neurons; Npy, neuropeptide Y inhibitory interneurons;
PN, projection neuron; LTMR, low-threshold mechanoreceptors; V, vertical cells; IIo, outer lamina II, IIi, inner lamina II; IIid, inner lamina II (dorsal);
IIiv, inner lamina II (ventral); Aβ, Aβ myelinated fibers; Aδ, Aδ myelinated fibers; C, C fibers. B Axonal sprouting and circuit functional
reorganization of S1 involving both intracortical neurons and projection neurons are at least partially responsible for inducing pain by non-
noxious stimuli. The continuous lines and arrows indicate allodynia-relevant circuits, and dotted lines indicate suppressed neuronal activity or
synaptic losses in the cause of enhanced pathology. Arrowheads indicate the direction of excitatory inputs. White circle (L5a) indicates decreased
neuronal hyperactivity after injury. L, layer; Pyr, pyramidal neurons; PV, parvalbumin-expressing neurons; SOM, somatostatin-expressing
interneurons; VIP, vasoactive intestinal polypeptide-expressing interneurons; PO, neurons from the thalamic posterior nucleus

the nucleus is thus considered the “higher-order nu- spine remodeling [31, 32] (Fig. 1B). Meanwhile, the ac-
cleus.” The PO nucleus is more heavily involved in nox- tivity of the layer 2/3 neuronal population of S1 acutely
ious stimuli mediation projecting exclusively from the increased when mice were injected with CFA into the
ventrobasalis (thalamic VB nuclei, including the VPL sole of the foot, inducing an inflammatory type pain.
and ventral posterior medial nucleus [VPM]) [22, 23]. The increase in synchronized neuronal activity in layer
Receiving inputs from the PO nucleus, S2L4 neurons 2/3 reduced with N-type calcium ion channel blockers,
process nociceptive stimuli, in response to peripheral and the pain level pacified, suggesting that the S1 layer
nerve injury in mice [24]. When VPL neurons were gen- 2/3 neurons mediate the pain level [33]. Whether it is
etically ablated at birth, S1L4 neurons can also become layer 2/3 or layer 5 pyramidal cells, S1 appears to
responsive to nociceptive stimuli, the layer that typically undergo plastic changes relevant to pain pathology asso-
responds to non-nociceptive stimuli [25]. Thus, the ciated with peripheral inflammation or peripheral neur-
identity of S1L4 neurons is not fully committed upon opathy. It appears that the projection from the thalamic
birth, and it is thought that thalamocortical input affects PO nucleus to the S1 cortex (PO-S1 both glutamatergic
the post-mitotic differentiation of S1L4 neurons [26]. neurons, POGlu -S1Glu) is implicated in neuropathic pain
The plasticity of PO neurons halts around postnatal day induced by either CFA or SNI injury models. Another
10 [25]. S1 plasticity also occurs as a consequence of an pathway of the parafascicular thalamic nucleus (PFGlu)
injury to the brain [27]. We showed ectopic collateral to the anterior cingulate cortex is implicated in inducing
sprouting from PO neurons in layer 4 of S1 instead of allodynia with depression-like symptoms [34]. Further
layer 5a, the layer to which PO neuronal axons typically research is warranted to investigate whether the unique
project after hemorrhage to the thalamic VPL nucleus in manifestations of pain pathogenesis could be explained
mice [5] (Fig. 1B). The mice showed a lowered threshold by the basis of neuronal circuits and that demonstration
in response to a mechanical stimulus, exhibiting signs of of post-injury ectopic somatosensory circuits may fur-
central post-stroke pain (CPSP). CPSP is commonly ob- ther elucidate the differential mechanisms of nociplastic
served in patients who suffered a stroke, the onset of pain and neuropathic pain.
which is late [28]. The post-stroke brain network
reorganization observed over time in stroke patients is Dynamic function of microglia in neuroplasticity
considered maladaptive, which relates to pain manifest- related to chronic pain
ation [29]. Microglia are known as tissue-resident macrophages of
Neuroplastic changes in S1 occur not only after injur- the CNS in the parenchyma of the brain and spinal cord.
ies to the thalamus but also after PNS injuries. In the A genetic fate mapping study using Runx1cre mouse lines
spared nerve injury (SNI) mouse model, which induces revealed that microglia are derived from yolk-sac erythro-
chronic pain, activities in S1 layer 5 (L5) pyramidal neu- myeloid progenitors (EMPs) [35] and that the origin of
rons persistently rise [30] (Fig. 1B). The activity elevation microglia particularly differs from that of perivascular,
is explained by the effect of less input from the dorsal meningeal, and choroid plexus macrophages [36, 37] (Fig.
horn, resulting in the hypoactivity of somatostatin 2). The microglial origin can also be separated from that
(SOM) neurons, acts in favor of pyramidal neuron of the other tissue-resident macrophages by the timing
hyperactivity. In vivo two-photon imaging experiments the cells migrate to each organ from the time point when
have also revealed that L5 pyramidal neurons of the S1 the blood-brain barrier is formed [38]. In addition, while
after peripheral nerve injury result in persistent dendritic other CNS tissue-resident macrophages differentiate in a
Hiraga et al. Inflammation and Regeneration (2022) 42:15 Page 5 of 10

Fig. 2 The origin of tissue-resident macrophages (microglia, perivascular/ meningeal/ choroid plexus macrophage) in the CNS. Tissue-resident
macrophages of the CNS in mammals are derived from three consecutive hematopoietic systems (primitive hematopoiesis, transient-definitive
hematopoiesis, definitive hematopoiesis) during embryogenesis. In mouse primitive hematopoiesis, erythro-myeloid progenitors (EMPs) occur in
the yolk sac of extraembryonic tissue during the embryonic period (E7-7.5), and primitive macrophages are produced from these EMPs
independently of the transcription factor Myb without going through monocytes. Primitive macrophages are then carried to each organ by the
circulatory system and engrafted before the formation of the blood-brain barrier. Microglia in the parenchyma of the brain and spinal cord
differentiate from these primitive macrophages. Around E9.5, yolk sac-derived EMPs migrate from the yolk sac to the fetal liver and initiate
transient-definitive hematopoiesis. Then, in transient-definitive hematopoiesis, monocytes are produced from EMPs in a Myb-dependent manner,
and the primitive macrophages previously engrafted in each organ are replaced. Since the blood-brain barrier is formed in the brain and
infiltration of these monocytes rarely occurs, only microglia present in the parenchyma of the brain and spinal cord are the main origins of
primitive macrophages derived in the yolk sac. Around E10.5, hematopoietic stem cells (HSCs) migrate to the fetal liver to start definitive
hematopoiesis. HSCs migrate from the fetal liver to the bone marrow before birth and supply the entire line of blood cells throughout life.
Choroid plexus macrophages derive from HSC-EMP or blood monocytes. Below the dotted line, microglia and CNS tissue-resident macrophages,
and common gene expression patterns are shown

Myb transcription factor-dependent manner, microglia pathological conditions, microglia change their morph-
differentiate independently of the Myb transcription factor ology to amoeboid shapes with shortened protrusions
[39], and the gene expression patterns between the two and enlarged cell body, indicating microglia are func-
cell types are distinguishable [40–45] (see Fig. 2). The tionally active, from their typical form of ramified shape
main function of microglia is to physically interact with with multiple finely branched protrusions on the small
synapses, debris, and extracellular matrix in phagocytosis cell. Reports have shown morphological changes of
[46–56], and to release humoral factors including neuro- microglia are associated with pain development [60],
trophic factors [57–59]. some of which could be through the release of humoral
While the microglia play an important role in the de- factors [32, 63, 64].
velopment and homeostasis of the nervous system, it has After PNS injury, microglial activation accompanied
been noted that abnormal microglial hyperactivity may by morphological changes can be observed well beyond
contribute to neuropathology [60–62]. Under various the spinal dorsal horn, including in the ventral tegmental
Hiraga et al. Inflammation and Regeneration (2022) 42:15 Page 6 of 10

area (VTA), the brainstem, and the hippocampus [65– to the nervous system, but cell proliferation and the release
67]. For example, ionized calcium-binding adaptor mol- of various humoral factors by microglia can take place with
ecule 1 (Iba1) immunoreactivity, which is indicative of or without distinctive morphological changes. Microglia
microglial activation, showed that microglia in the VTA without obvious morphological changes have been shown
increased after a PNS injury in the disruption of the in the amygdala and the somatosensory cortex after nerve
mesolimbic reward circuit [65]. The circuit disruption injury, and these microglia have been reported to regulate
reduced the dopamine release from the limbic dopamin- neuropathic pain [32, 68]. Hence, the absence of morpho-
ergic neurons that project from the VTA of the mid- logical activation in microglia does not always indicate a
brain to the nucleus accumbens (NAc) of the ventral lack of functional involvement.
striatum, affecting the emotional aspect of pain. It was, Microglia are said to be derived from the yolk sac;
therefore, suggested that such remote microglial func- however, in the rise of pain occurrence, it has been
tions may underlie morphine-resistant pain sensations. shown that circulating monocytes infiltrate into the par-
The microglia local to the brainstem also function as a enchyma of the spinal dorsal horn and differentiate into
remote control mechanism for thalamic map the functional microglia-like cells [69]. Chronically, infil-
reorganization that underlies the pathophysiology of tration of these circulating monocytes has also been ob-
neuropathic pain. A unilateral increase in Iba-1- served in the central nucleus of the amygdala (CeA) of
immunoreactivity (activated microglia) was evident in pain model mice after partial sciatic nerve ligation, and
the ipsilateral brainstem principal trigeminal nucleus it was shown that anxiety-like behavior was also induced
(Pr5) where axonal sprouting occurred projecting to the [68]. The study showed that bone marrow (BM)-derived
thalamic ventral posteromedial nucleus (VPM), but not microglia in CeA increased the levels of interleukin (IL)-
in the whisker region (barreloids) of the thalamic ventral 1b and C-C chemokine receptor type 2 (CCR2). The
posteromedial nucleus (VPM) connected to the injury suppression of BM microglial infiltration with the oral
site, the infraorbital nerve, in IONC mouse model. Such administration of a CCR2 antagonist relieved both pain
IONC induced new axonal innervations from Pr5 to in- and anxiety-like behavior; however, the direct micro-
dividual VPM neurons, as well as heightened Iba-1 im- injection of an IL-1b receptor antagonist into CeA re-
munoreactivity, accompanied by pain behavior. These sulted in only a slight improvement in pain behavior,
injury-induced effects were all suppressed by the system- but a complete reduction in anxiety-like behavior. The
atic microglial depletion with the oral administration of study showed BM-derived microglia specifically medi-
PLX3397, an inhibitor of c-kit and colony-stimulating ated anxiety-like behavior, along with modulating pain
factor 1 receptors (CSF1Rs) [66], suggesting that micro- development after PNS injury [4, 68].
glia is involved in the ectopic sprouting and pain behav- Other more recent studies have shown, however, the
ior. Another study showed a partial injury to the sciatic origin of microglia after a nerve injury is unlikely to be
nerve activated microglia and induced synaptic changes derived from circulating monocytes. Studies using mild
both remotely in the spinal dorsal horn and hippocam- irradiation, parabiosis mice, and CCRRFP/+-CX3CR1GFP/
+
pus. Pharmacological inhibition and genetic ablation of mice have indicated that BM-derived microglia were
microglia result in a reversal of region-specific synaptic not observed in the parenchyma of the CNS even after
plasticity and memory impairment induced by PNS in- nerve injuries [70, 71]. Thus, it is possible the microglia
jury. The results revealed how a PNS injury can affect that increase in the CNS parenchyma in the neuropathic
memory with simultaneously evolving chronic pain pain mouse model are the ones that reside locally. Fur-
pathophysiology, at least in part, through microglial ther studies should show how microglia come about to
function [67]. We have also obtained results that pain the damaged tissues.
can be modulated by the regulation of remote microglial One of the property changes in microglia is the release
function. Morphologically altered microglia were present of brain-derived neurotrophic factor (BDNF) following
for up to 7 days not only in the thalamus, the core dam- PNS injury. Specifically, synaptic remodeling and pyram-
aged by a hemorrhagic injury, but also found in the S1 idal neuron hyperactivity in the S1 cortex induced by
[5]. The activated microglia in S1 were shown to con- nerve injury can be altered by the depletion of
tribute to ectopic axonal reorganization of the PO-S1L4 microglial-specific BDNF [32]. The specific depletion of
circuit, and to modulation of pain behavior. With the BDNF in S1 microglia can also suppress pain behavior
administration of a microglial inhibitor, ectopic sprout- developed by PNS injury, suggesting that microglia
ing and pain behavior were reversed to a non-injury modulate pain-related neuroplasticity through the re-
level, suggesting that microglial function in S1 plasticity lease of a growth factor. The mechanism of BDNF re-
probably induced nociplastic pain. leased from microglia in pain development is through
Microglia can polarize from the form of ramified shape altering structure and function of synapses that cause in-
to the active form of amoeboid shape triggered by a damage creased presynaptic terminals and post-neuron
Hiraga et al. Inflammation and Regeneration (2022) 42:15 Page 7 of 10

hyperexcitability [4, 64, 72] (Fig. 3). The source of BDNF neuropathic injury areas [5, 77–80]. In the future, fur-
is likely to be P2X4-expressing microglia [64]. P2X4 is ther analyses are warranted on how microglia induce
one of the ATP receptors, which could be a molecular and regulate structural and functional synaptic plasticity
mechanism common to spinal cord microglia. through these and other factors in pain development.
Furthermore, IL-10 secreted from microglia is shown Together, mounting evidence suggests that cerebral
to contribute to synapse formation [73], which increases microglia participate in nociplastic changes in distant
pain pathology [5]. Hence, IL-10 may be another factor brain regions to an injury core. Identifying the detailed
that connects synaptic plasticity and pain development. cellular or molecular microglial functions responsible for
It has been shown IL-10 is released from TREM2- inducing neuroplasticity may yield a pharmacological
regulated anti-inflammatory microglia [74, 75]. Cx3CR1, target for treating chronic pain.
P2Y12, C1q, and TREM2, are also factors that are asso-
ciated with synapse formation and elimination, or debris Conclusions
removal contributing to pain behavior [47, 50, 51, 53, Further elucidation of post-injury ectopic somatosensory
76], whose expression levels increase in and around the circuits may help categorize the mechanisms underlying

Physical interaction Humoral factor release

Contact with neurons, axons, synapses Synaptic remodeling, neuronal hyperactivity
neuronal debris and amyloid Microglia neuronal survival, neurogenesis

Morphological change Morphological/Functional change Functional change

TREM2 P2X4

TREM2

Cytokine secretion
and debris removal in neuropathic pain
BDNF Synaptic remodeling
Possibility of pain development through
synapse formation/elimination and debris removal KCC2

Synapse TREM2 TrkB

Cl- [Cl-

GABAA/Glycine
receptor
Synapse BDNF Debris Hyperexcitability
SDH neuron Pyramidal neuron

Fig. 3 Microglial modulation of neuroplasticity in the spinal dorsal horn and S1 that underlies chronic pain after PNS or CNS injury. TOP: the
physical interaction and humoral factor release. BOTTOM: morphological and functional changes in microglia after PNS or CNS injury. Studies
showing morphological changes in microglia have not shown specific functions, but have suggested their involvements in the pain development
based on the molecular functions. Functional changes in microglia have been suggested to be factors released via TREM2/DAP12 or P2X4 signals.
BDNF is one factor shown to be secreted from microglia in the spinal cord and brain after PNS or CNS injury, involved in pain development
through synaptic remodeling and inducing hyperexcitability
Hiraga et al. Inflammation and Regeneration (2022) 42:15 Page 8 of 10

nociceptive, neuropathic, and nociplastic-type pain. 5. Hiraga SI, Itokazu T, Hoshiko M, Takaya H, Nishibe M, Yamashita T. Microglial
Studies employing cellular and molecular approaches, depletion under thalamic hemorrhage ameliorates mechanical allodynia
and suppresses aberrant axonal sprouting. JCI Insight. 2020;5(3). https://doi.
including neuron type-specific pharmacological molecu- org/10.1172/jci.insight.131801.
lar inhibition or neuron type-specific genetic ablation, 6. Gutierrez-Mecinas M, Kuehn ED, Abraira VE, Polgar E, Watanabe M, Todd AJ.
are expected to contribute to the development of a ther- Immunostaining for Homer reveals the majority of excitatory synapses in
laminae I-III of the mouse spinal dorsal horn. Neuroscience. 2016;329:171–
apy targeting neuroplasticity that induces chronic pain 81. https://doi.org/10.1016/j.neuroscience.2016.05.009.
in response to PNS or CNS injury. Among the various 7. Gutierrez-Mecinas M, Bell AM, Shepherd F, Polgar E, Watanabe M,
functions of microglia, one prominent function seems to Furuta T, et al. Expression of cholecystokinin by neurons in mouse
spinal dorsal horn. J Comp Neurol. 2019;527(11):1857–71. https://doi.
be pain regulation in the PNS and CNS. Microglia may org/10.1002/cne.24657.
directly contribute to synaptic remodeling and altering 8. Hayano Y, Takasu K, Koyama Y, Yamada M, Ogawa K, Minami K, et al. Dorsal
pain circuits, or contribute indirectly to neuroplasticity horn interneuron-derived Netrin-4 contributes to spinal sensitization in
chronic pain via Unc5B. J Exp Med. 2016;213(13):2949–66. https://doi.org/1
through property changes, including the release of 0.1084/jem.20160877.
growth factors. Hence, further elucidation of the modu- 9. Sathyamurthy A, Johnson KR, Matson KJE, Dobrott CI, Li L, Ryba AR, et al.
latory mechanisms of microglia, including a specific Massively parallel single nucleus transcriptional profiling defines spinal cord
neurons and their activity during behavior. Cell Rep. 2018;22(8):2216–25.
gene-regulating microglial function or cytokines and https://doi.org/10.1016/j.celrep.2018.02.003.
growth factors released to affect neuroplasticity, may 10. Abraira VE, Kuehn ED, Chirila AM, Springel MW, Toliver AA, Zimmerman AL,
lead to a therapeutic approach that addresses et al. The cellular and synaptic architecture of the mechanosensory dorsal
horn. Cell. 2017;168(1-2):295–310 e219. https://doi.org/10.1016/j.cell.2016.12.
neuroplasticity-relevant chronic pain. 010.
11. Haring M, Zeisel A, Hochgerner H, Rinwa P, Jakobsson JET, Lonnerberg P,
Authors’ contributions
et al. Neuronal atlas of the dorsal horn defines its architecture and links
S.H wrote the manuscript and T.I., M.N., and T.Y. revised it. The author(s) read
sensory input to transcriptional cell types. Nat Neurosci. 2018;21(6):869–80.
and approved the final manuscript.
https://doi.org/10.1038/s41593-018-0141-1.
12. Peirs C, Williams SG, Zhao X, Arokiaraj CM, Ferreira DW, Noh MC, et al.
Funding
Mechanical allodynia circuitry in the dorsal horn is defined by the nature of
Not applicable
the injury. Neuron. 2021;109(1):73–90 e77. https://doi.org/10.1016/j.neuron.2
020.10.027.
Availability of data and materials
Not applicable 13. Miraucourt LS, Dallel R, Voisin DL. Glycine inhibitory dysfunction turns touch
into pain through PKCgamma interneurons. PLoS One. 2007;2(11):e1116.
Declarations https://doi.org/10.1371/journal.pone.0001116.
14. Lu Y, Dong H, Gao Y, Gong Y, Ren Y, Gu N, et al. A feed-forward spinal cord
Ethics approval and consent to participate glycinergic neural circuit gates mechanical allodynia. J Clin Invest. 2013;
Not applicable 123(9):4050–62. https://doi.org/10.1172/JCI70026.
15. Petitjean H, Pawlowski SA, Fraine SL, Sharif B, Hamad D, Fatima T, et al.
Consent for publication Dorsal horn parvalbumin neurons are gate-keepers of touch-evoked pain
All the authors agree for publication of this manuscript. after nerve injury. Cell Rep. 2015;13(6):1246–57. https://doi.org/10.1016/j.
celrep.2015.09.080.
Competing interests 16. Peirs C, Williams SP, Zhao X, Walsh CE, Gedeon JY, Cagle NE, et al. Dorsal
The authors declare that they have no competing interests. horn circuits for persistent mechanical pain. Neuron. 2015;87(4):797–812.
https://doi.org/10.1016/j.neuron.2015.07.029.
Author details 17. Boyle KA, Gradwell MA, Yasaka T, Dickie AC, Polgar E, Ganley RP, et al.
1
Department of Neuro-Medical Science, Graduate School of Medicine, Osaka Defining a spinal microcircuit that gates myelinated afferent input:
University, Suita, Osaka, Japan. 2Department of Molecular Neuroscience, implications for tactile allodynia. Cell Rep. 2019;28(2):526–40 e526. https://
Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. 3Center doi.org/10.1016/j.celrep.2019.06.040.
for Strategic Innovative Dentistry, Graduate School of Dentistry, Osaka 18. Alba-Delgado C, Mountadem S, Mermet-Joret N, Monconduit L, Dallel R,
University, Suita, Osaka, Japan. 4WPI Immunology Frontier Research Center, Artola A, et al. 5-HT(2A) receptor-induced morphological reorganization of
Osaka, Japan. 5Graduate School of Frontier Biosciences, Osaka University, PKCγ-expressing interneurons gates inflammatory mechanical allodynia in
Osaka, Japan. rat. J Neurosci. 2018;38(49):10489–504. https://doi.org/10.1523/jneurosci.12
94-18.2018.
Received: 21 October 2021 Accepted: 19 February 2022 19. Tashima R, Koga K, Yoshikawa Y, Sekine M, Watanabe M, Tozaki-Saitoh H,
et al. A subset of spinal dorsal horn interneurons crucial for gating touch-
evoked pain-like behavior. Proc Natl Acad Sci U S A. 2021;118(3). https://doi.
References org/10.1073/pnas.2021220118.
1. Jensen TS, Baron R, Haanpaa M, Kalso E, Loeser JD, Rice ASC, et al. A new 20. Polgar E, Sardella TC, Watanabe M, Todd AJ. Quantitative study of NPY-
definition of neuropathic pain. Pain. 2011;152(10):2204–5. https://doi.org/1 expressing GABAergic neurons and axons in rat spinal dorsal horn. J Comp
0.1016/j.pain.2011.06.017. Neurol. 2011;519(6):1007–23. https://doi.org/10.1002/cne.22570.
2. Fitzcharles MA, Cohen SP, Clauw DJ, Littlejohn G, Usui C, Hauser W. 21. Todd AJ. Neuronal circuitry for pain processing in the dorsal horn. Nat Rev
Nociplastic pain: towards an understanding of prevalent pain conditions. Neurosci. 2010;11(12):823–36. https://doi.org/10.1038/nrn2947.
Lancet. 2021;397(10289):2098–110. https://doi.org/10.1016/S0140-6736(21 22. Wimmer VC, Bruno RM, de Kock CP, Kuner T, Sakmann B. Dimensions of a
)00392-5. projection column and architecture of VPM and POm axons in rat vibrissal
3. Chen G, Zhang YQ, Qadri YJ, Serhan CN, Ji RR. Microglia in pain: detrimental cortex. Cereb Cortex. 2010;20(10):2265–76. https://doi.org/10.1093/cercor/
and protective roles in pathogenesis and resolution of pain. Neuron. 2018; bhq068.
100(6):1292–311. https://doi.org/10.1016/j.neuron.2018.11.009. 23. Ohno S, Kuramoto E, Furuta T, Hioki H, Tanaka YR, Fujiyama F, et al. A
4. Inoue K, Tsuda M. Microglia in neuropathic pain: cellular and molecular morphological analysis of thalamocortical axon fibers of rat posterior
mechanisms and therapeutic potential. Nat Rev Neurosci. 2018;19(3):138–52. thalamic nuclei: a single neuron tracing study with viral vectors. Cereb
https://doi.org/10.1038/nrn.2018.2. Cortex. 2012;22(12):2840–57. https://doi.org/10.1093/cercor/bhr356.
Hiraga et al. Inflammation and Regeneration (2022) 42:15 Page 9 of 10

24. Frangeul L, Porrero C, Garcia-Amado M, Maimone B, Maniglier M, Clasca 43. Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK,
F, et al. Specific activation of the paralemniscal pathway during et al. The microglial sensome revealed by direct RNA sequencing. Nat
nociception. Eur J Neurosci. 2014;39(9):1455–64. https://doi.org/10.1111/ Neurosci. 2013;16(12):1896–905. https://doi.org/10.1038/nn.3554.
ejn.12524. 44. MJC J, Sankowski R, Brendecke SM, Sagar LG, Tai YH, et al. Single-cell
25. Pouchelon G, Gambino F, Bellone C, Telley L, Vitali I, Luscher C, et al. profiling identifies myeloid cell subsets with distinct fates during
Modality-specific thalamocortical inputs instruct the identity of postsynaptic neuroinflammation. Science. 2019;363(6425). https://doi.org/10.1126/
L4 neurons. Nature. 2014;511(7510):471–4. https://doi.org/10.1038/nature133 science.aat7554.
90. 45. Mrdjen D, Pavlovic A, Hartmann FJ, Schreiner B, Utz SG, Leung BP, et al.
26. De la Rossa A, Bellone C, Golding B, Vitali I, Moss J, Toni N, et al. In vivo High-dimensional single-cell mapping of central nervous system immune
reprogramming of circuit connectivity in postmitotic neocortical neurons. cells reveals distinct myeloid subsets in health, aging, and disease.
Nat Neurosci. 2013;16(2):193–200. https://doi.org/10.1038/nn.3299. Immunity. 2018;48(2):380–95 e386. https://doi.org/10.1016/j.immuni.2018.01.
27. Croquelois A, Bronchti G, Welker E. Cortical origin of functional recovery in 011.
the somatosensory cortex of the adult mouse after thalamic lesion. Eur J 46. Farfara D, Trudler D, Segev-Amzaleg N, Galron R, Stein R, Frenkel D. gamma-
Neurosci. 2005;21(7):1798–806. https://doi.org/10.1111/j.1460-9568.2005.03 Secretase component presenilin is important for microglia beta-amyloid
994.x. clearance. Ann Neurol. 2011;69(1):170–80. https://doi.org/10.1002/ana.22191.
28. Andersen G, Vestergaard K, Ingeman-Nielsen M, Jensen TS. Incidence of 47. Filipello F, Morini R, Corradini I, Zerbi V, Canzi A, Michalski B, et al. The
central post-stroke pain. Pain. 1995;61(2):187–93. https://doi.org/10.1016/03 Microglial innate immune receptor TREM2 is required for synapse
04-3959(94)00144-4. elimination and normal brain connectivity. Immunity. 2018;48(5):979–91
29. Hosomi K, Seymour B, Saitoh Y. Modulating the pain network-- e978. https://doi.org/10.1016/j.immuni.2018.04.016.
neurostimulation for central poststroke pain. Nat Rev Neurol. 2015;11(5): 48. Marin-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M.
290–9. https://doi.org/10.1038/nrneurol.2015.58. Microglia promote the death of developing Purkinje cells. Neuron. 2004;
30. Cichon J, Blanck TJJ, Gan WB, Yang G. Activation of cortical somatostatin 41(4):535–47. https://doi.org/10.1016/s0896-6273(04)00069-8.
interneurons prevents the development of neuropathic pain. Nat Neurosci. 49. Nguyen PT, Dorman LC, Pan S, Vainchtein ID, Han RT, Nakao-Inoue H, et al.
2017;20(8):1122–32. https://doi.org/10.1038/nn.4595. Microglial remodeling of the extracellular matrix promotes synapse
31. Kim SK, Hayashi H, Ishikawa T, Shibata K, Shigetomi E, Shinozaki Y, et al. plasticity. Cell. 2020;182(2):388–403 e315. https://doi.org/10.1016/j.cell.2020.
Cortical astrocytes rewire somatosensory cortical circuits for peripheral 05.050.
neuropathic pain. J Clin Invest. 2016;126(5):1983–97. https://doi.org/10.1172/ 50. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, et al.
JCI82859. Synaptic pruning by microglia is necessary for normal brain development.
32. Huang L, Jin J, Chen K, You S, Zhang H, Sideris A, et al. BDNF produced by Science. 2011;333(6048):1456–8. https://doi.org/10.1126/science.1202529.
cerebral microglia promotes cortical plasticity and pain hypersensitivity after 51. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R,
peripheral nerve injury. PLoS Biol. 2021;19(7):e3001337. https://doi.org/10.13 et al. Microglia sculpt postnatal neural circuits in an activity and
71/journal.pbio.3001337. complement-dependent manner. Neuron. 2012;74(4):691–705. https://doi.
33. Okada T, Kato D, Nomura Y, Obata N, Quan X, Morinaga A, et al. Pain org/10.1016/j.neuron.2012.03.026.
induces stable, active microcircuits in the somatosensory cortex that 52. Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-
provide a therapeutic target. Sci Adv. 2021;7(12). https://doi.org/10.1126/scia Wadiche LS, et al. Microglia shape adult hippocampal neurogenesis through
dv.abd8261. apoptosis-coupled phagocytosis. Cell Stem Cell. 2010;7(4):483–95. https://
34. Zhu X, Tang HD, Dong WY, Kang F, Liu A, Mao Y, et al. Distinct doi.org/10.1016/j.stem.2010.08.014.
thalamocortical circuits underlie allodynia induced by tissue injury and by 53. Sipe GO, Lowery RL, Tremblay ME, Kelly EA, Lamantia CE, Majewska AK.
depression-like states. Nat Neurosci. 2021;24(4):542–53. https://doi.org/10.1 Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex.
038/s41593-021-00811-x. Nat Commun. 2016;7:10905. https://doi.org/10.1038/ncomms10905.
35. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate 54. Takahashi K, Rochford CD, Neumann H. Clearance of apoptotic neurons
mapping analysis reveals that adult microglia derive from primitive without inflammation by microglial triggering receptor expressed on
macrophages. Science. 2010;330(6005):841–5. https://doi.org/10.1126/ myeloid cells-2. J Exp Med. 2005;201(4):647–57. https://doi.org/10.1084/jem.2
science.1194637. 0041611.
36. Hoeffel G, Chen J, Lavin Y, Low D, Almeida FF, See P, et al. C-Myb(+) 55. Cunningham CL, Martinez-Cerdeno V, Noctor SC. Microglia regulate the
erythro-myeloid progenitor-derived fetal monocytes give rise to adult number of neural precursor cells in the developing cerebral cortex. J
tissue-resident macrophages. Immunity. 2015;42(4):665–78. https://doi.org/1 Neurosci. 2013;33(10):4216–33. https://doi.org/10.1523/JNEUROSCI.3441-12.2
0.1016/j.immuni.2015.03.011. 013.
37. Stremmel C, Schuchert R, Wagner F, Thaler R, Weinberger T, Pick R, et al. 56. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N,
Yolk sac macrophage progenitors traffic to the embryo during defined et al. The classical complement cascade mediates CNS synapse elimination.
stages of development. Nat Commun. 2018;9(1):75. https://doi.org/10.1038/ Cell. 2007;131(6):1164–78. https://doi.org/10.1016/j.cell.2007.10.036.
s41467-017-02492-2. 57. Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR 3rd, Lafaille JJ, et al.
38. Daneman R, Zhou L, Kebede AA, Barres BA. Pericytes are required for blood- Microglia promote learning-dependent synapse formation through brain-
brain barrier integrity during embryogenesis. Nature. 2010;468(7323):562–6. derived neurotrophic factor. Cell. 2013;155(7):1596–609. https://doi.org/10.1
https://doi.org/10.1038/nature09513. 016/j.cell.2013.11.030.
39. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, 58. Shigemoto-Mogami Y, Hoshikawa K, Goldman JE, Sekino Y, Sato K. Microglia
Kierdorf K, et al. A lineage of myeloid cells independent of Myb and enhance neurogenesis and oligodendrogenesis in the early postnatal
hematopoietic stem cells. Science. 2012;336(6077):86–90. https://doi.org/1 subventricular zone. J Neurosci. 2014;34(6):2231–43. https://doi.org/10.1523/
0.1126/science.1219179. JNEUROSCI.1619-13.2014.
40. Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, et al. Gene- 59. Ueno M, Fujita Y, Tanaka T, Nakamura Y, Kikuta J, Ishii M, et al. Layer V
expression profiles and transcriptional regulatory pathways that underlie the cortical neurons require microglial support for survival during postnatal
identity and diversity of mouse tissue macrophages. Nat Immunol. 2012; development. Nat Neurosci. 2013;16(5):543–51. https://doi.org/10.1038/nn.33
13(11):1118–28. https://doi.org/10.1038/ni.2419. 58.
41. Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL, Fernhoff NB, 60. Prinz M, Jung S, Priller J. Microglia biology: one century of evolving
et al. New tools for studying microglia in the mouse and human CNS. Proc concepts. Cell. 2019;179(2):292–311. https://doi.org/10.1016/j.cell.2019.08.053.
Natl Acad Sci U S A. 2016;113(12):E1738–46. https://doi.org/10.1073/pnas.1 61. Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective
525528113. beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J
42. Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Neurosci. 2008;28(33):8354–60. https://doi.org/10.1523/JNEUROSCI.0616-08.2
et al. Identification of a unique TGF-beta-dependent molecular and 008.
functional signature in microglia. Nat Neurosci. 2014;17(1):131–43. https:// 62. Zhang S, Wang XJ, Tian LP, Pan J, Lu GQ, Zhang YJ, et al. CD200-CD200R
doi.org/10.1038/nn.3599. dysfunction exacerbates microglial activation and dopaminergic
Hiraga et al. Inflammation and Regeneration (2022) 42:15 Page 10 of 10

neurodegeneration in a rat model of Parkinson’s disease. J Publisher’s Note

Neuroinflammation. 2011;8:154. https://doi.org/10.1186/1742-2094-8-154. Springer Nature remains neutral with regard to jurisdictional claims in
63. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, et al. BDNF from published maps and institutional affiliations.
microglia causes the shift in neuronal anion gradient underlying
neuropathic pain. Nature. 2005;438(7070):1017–21. https://doi.org/10.1038/
nature04223.
64. Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter
MW, et al. P2X4 receptors induced in spinal microglia gate tactile allodynia
after nerve injury. Nature. 2003;424(6950):778–83. https://doi.org/10.1038/na
ture01786.
65. Taylor AM, Castonguay A, Taylor AJ, Murphy NP, Ghogha A, Cook C, et al.
Microglia disrupt mesolimbic reward circuitry in chronic pain. J Neurosci.
2015;35(22):8442–50. https://doi.org/10.1523/JNEUROSCI.4036-14.2015.
66. Ueta Y, Miyata M. Brainstem local microglia induce whisker map plasticity in
the thalamus after peripheral nerve injury. Cell Rep. 2021;34(10):108823.
https://doi.org/10.1016/j.celrep.2021.108823.
67. Liu Y, Zhou LJ, Wang J, Li D, Ren WJ, Peng J, et al. TNF-alpha differentially
regulates synaptic plasticity in the hippocampus and spinal cord by
microglia-dependent mechanisms after peripheral nerve injury. J Neurosci.
2017;37(4):871–81. https://doi.org/10.1523/JNEUROSCI.2235-16.2016.
68. Sawada A, Niiyama Y, Ataka K, Nagaishi K, Yamakage M, Fujimiya M.
Suppression of bone marrow-derived microglia in the amygdala
improves anxiety-like behavior induced by chronic partial sciatic nerve
ligation in mice. Pain. 2014;155(9):1762–72. https://doi.org/10.1016/j.pa
in.2014.05.031.
69. Zhang J, Shi XQ, Echeverry S, Mogil JS, De Koninck Y, Rivest S. Expression of
CCR2 in both resident and bone marrow-derived microglia plays a critical
role in neuropathic pain. J Neurosci. 2007;27(45):12396–406. https://doi.
org/10.1523/JNEUROSCI.3016-07.2007.
70. Gu N, Peng J, Murugan M, Wang X, Eyo UB, Sun D, et al. Spinal microgliosis
due to resident microglial proliferation is required for pain hypersensitivity
after peripheral nerve injury. Cell Rep. 2016;16(3):605–14. https://doi.org/10.1
016/j.celrep.2016.06.018.
71. Tashima R, Mikuriya S, Tomiyama D, Shiratori-Hayashi M, Yamashita T, Kohro
Y, et al. Bone marrow-derived cells in the population of spinal microglia
after peripheral nerve injury. Sci Rep. 2016;6:23701. https://doi.org/10.1038/
srep23701.
72. Zhou LJ, Peng J, Xu YN, Zeng WJ, Zhang J, Wei X, et al. Microglia are
indispensable for synaptic plasticity in the spinal dorsal horn and chronic
pain. Cell Rep. 2019;27(13):3844–59 e3846. https://doi.org/10.1016/j.celrep.2
019.05.087.
73. Lim SH, Park E, You B, Jung Y, Park AR, Park SG, et al. Neuronal synapse
formation induced by microglia and interleukin 10. PLoS One. 2013;8(11):
e81218. https://doi.org/10.1371/journal.pone.0081218.
74. Liu W, Taso O, Wang R, Bayram S, Graham AC, Garcia-Reitboeck P, et al.
Trem2 promotes anti-inflammatory responses in microglia and is
suppressed under pro-inflammatory conditions. Hum Mol Genet. 2020;
29(19):3224–48. https://doi.org/10.1093/hmg/ddaa209.
75. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage
activation. Nat Rev Immunol. 2008;8(12):958–69. https://doi.org/10.1038/
nri2448.
76. Rogers JT, Morganti JM, Bachstetter AD, Hudson CE, Peters MM, Grimmig
BA, et al. CX3CR1 deficiency leads to impairment of hippocampal cognitive
function and synaptic plasticity. J Neurosci. 2011;31(45):16241–50. https://
doi.org/10.1523/JNEUROSCI.3667-11.2011.
77. Asano S, Hayashi Y, Iwata K, Okada-Ogawa A, Hitomi S, Shibuta I, et al.
Microglia-astrocyte communication via C1q contributes to orofacial
neuropathic pain associated with infraorbital nerve injury. Int J Mol Sci.
2020;21(18). https://doi.org/10.3390/ijms21186834.
78. Gu N, Eyo UB, Murugan M, Peng J, Matta S, Dong H, et al. Microglial P2Y12
receptors regulate microglial activation and surveillance during neuropathic
pain. Brain Behav Immun. 2016;55:82–92. https://doi.org/10.1016/j.bbi.201
5.11.007.
79. Kobayashi M, Konishi H, Sayo A, Takai T, Kiyama H. TREM2/DAP12 signal
elicits proinflammatory response in microglia and exacerbates neuropathic
pain. J Neurosci. 2016;36(43):11138–50. https://doi.org/10.1523/
JNEUROSCI.1238-16.2016.
80. Lindia JA, McGowan E, Jochnowitz N, Abbadie C. Induction of CX3CL1
expression in astrocytes and CX3CR1 in microglia in the spinal cord of a rat
model of neuropathic pain. J Pain. 2005;6(7):434–8. https://doi.org/10.1016/j.
jpain.2005.02.001.