See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/5939592

Neurotransmitter receptors on microglia

Article  in  Trends in Neurosciences · November 2007

DOI: 10.1016/j.tins.2007.07.007 · Source: PubMed

CITATIONS READS

493 887

2 authors:

Jennifer M Pocock Helmut Kettenmann

University College London Max-Delbrück-Centrum für Molekulare Medizin
110 PUBLICATIONS   6,289 CITATIONS    472 PUBLICATIONS   38,421 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Invasion of glioblastoma multiforme View project

Cortical Spreading Depression View project

All content following this page was uploaded by Jennifer M Pocock on 31 July 2018.

The user has requested enhancement of the downloaded file.

 Review TRENDS in Neurosciences
Neurotransmitter receptors on
microglia
Jennifer M Pocock1 and Helmut Kettenmann2
1
Cell Signalling Laboratory, Department of Neuroinflammation, Institute of Neurology, University College London, 1 Wakefield
Street, London WC1N 1PJ, UK
2
Cellular Neuroscience, Max Delbrück Center, Robert-Rössle Str. 10, D-13092 Berlin, Germany
Microglia are the intrinsic immune cells of the brain and
express chemokine and cytokine receptors that interact
with the peripheral immune cells. Recent studies have
indicated that microglia also respond to the brain’s
classical signalling substances, the neurotransmitters.
Here, we review the evidence for the expression of
neurotransmitter receptors on microglia and the con-
sequences of this receptor activation for microglial beha-
viour. It is evident that neurotransmitters instruct
microglia to perform distinct types of responses, such
as triggering an inflammatory cascade or acquiring a
neuroprotective phenotype. Understanding how micro-
glia respond to different neurotransmitters will thus
have important implications for controlling the reactivity
of these cells in acute injury, as well as for treating
chronic neurodegenerative diseases.
Introduction
Microglia are present in all regions of the central nervous
system (CNS), although their density varies in different
brain regions [1]. Microglia, first described by Rı́o- Hortega
[2] and characterized by a small soma and several highly
branched processes, are derived from the myelomonocytic
lineage and invade the CNS tissue at both embryonic and
postnatal stages (for reviews, see [3,4]). These microglial
precursors possess an ameboid morphology and actively
migrate within the brain parenchyma to colonize all
regions of the brain. Microglia acquire a highly ramified
morphology in the healthy adult brain; microglia in this
form are termed ‘resting microglia’. [5]. When one observes
the morphology of resting microglia, it is evident that each
cell has a territory that it covers with its highly branched
processes. Two recent reports have noted that these pro-
cesses are highly motile; in fact, they are the most dynamic
structures in the CNS [6,7]. This process movement could
be viewed as a constant survey of the microglial cell’s
territory, and these cells should perhaps be termed ‘sur-
veying’ than ‘resting’ microglia (Figures 1–3).
The majority of previous studies on microglia have been
concerned with their role in pathology (for a review, see
[3]). Microglia are the first elements to respond after any
kind of disturbance in the brain. They undergo a trans-
formation, also termed microglial activation, that can hap-
pen within a few hours and last many days. One feature of
Corresponding authors: Pocock, J.M. (j.pocock@ion.ucl.ac.uk);
Kettenmann, H. (kettenmann@mdc-berlin.de).
Available online 29 September 2007.
www.sciencedirect.com 0166-2236/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2007.07.007
Vol.30 No.10
this activation process is the transformation of the cells
into an ameboid morphology that is similar to that of the
initial infiltrating precursors. Depending on the pathologic
stimulus, the activated microglia might proliferate,
migrate toward injured or damaged areas and/or be
induced to release many factors, such as cytokines or
reactive oxygen species (ROS), that affect the pathologic
process. Microglia are antigen-presenting cells because
they express proteins of the MHC-II complex and are,
thereby, interaction partners with infiltrating T lympho-
cytes. They express a wide array of characteristic immune-
cell receptors, such as chemokine and cytokine receptors
and receptors of the complement-factor family. Thus,
microglia have been viewed as intrinsic immune cells,
but they have not been considered as normal communi-
cation partners within the neuronal network. Functional
synapses have recently been discovered on subtypes of
astrocytes [8], but there is no evidence so far to suggest
that microglia might receive synaptic input.
In the following discussion, we will, however, summar-
ize the evidence that microglia can express a variety of
different classical neurotransmitter receptors that were
originally thought to be specific for neurons but in the
interim have been widely described in macroglial cells
(astrocytes and oligodendrocytes). Synaptic structures
are missing on microglia, so how can microglial trans-
mitter receptors be activated? In 1995, Agnati and Fuxe
proposed a model of ‘volume transmission’, as opposed to
‘wiring transmission’ [9,10]. In this model, neuroactive
substances are not only strictly confined to the synaptic
cleft but can also diffuse in the extracellular space and
activate extrasynaptic receptors. Indeed, neurons
express transmitter receptors not only at the postsyn-
aptic density but also at the presynapse and other regions
of the cell. It has been recognized that these extra-
synaptic receptors serve many regulatory roles in the
neuronal network. This makes it increasingly likely
that neurotransmitter receptors are also activated on
microglia because of the diffusion of transmitters in the
extracellular space.
Ionotropic glutamate receptors (iGluRs) can modulate
tumour-necrosis factor a (TNFa) release
Glutamate is the major excitatory neurotransmitter of the
CNS, and pertubations in the homeostasis of this trans-
mitter have been reported in neurodegenerative diseases.
The main functional iGluRs in cultured rat microglia are
528 Review TRENDS in Neurosciences Vol.30 No.10

Figure 1. Microglia in tissue and in culture. Microglia are activated by pathological events. The cells transform from a ramified morphology (a) into an ameboid form (b).
The cell shown in (a) was injected with Lucifer Yellow after membrane currents were recorded with the patch clamp technique from an acute slice [37]. The ramified
microglia in (a) was located in the facial nucleus and was injected two days after facial-nerve axotomy [89]. (c) shows microglia isolated from rat brain and
cultured in vitro for one day [19]. However, because no culture conditions can mimic the normal brain, there is no equivalent to the in vivo resting morphology of
microglia. Thus, cultured cells are always in an alerted state. Defined stimuli, such as bacterial components, LPS in particular, lead to a further activation of the cultured
cells, as shown in (d) (cultured rat-brain microglia exposed to 1 mg/ml LPS for 24 h). Activation is accompanied by a change in morphology. The scale bar for (a), (b) and
(d) represents 10 mm.

mostly AMPA (D,L-a-amino-3-hydroxy-5-methyl-4-isoxa- Metabotropic glutamate receptors (mGluRs) mediate

zole propionic acid)-type GluRs (GluRs 1–3, mainly in the
flip form) rather than kainate receptors [11,12]. Whereas
glutamate or kainate can trigger TNFa release, AMPA
receptor agonists inhibit it; unexpectedly, cyclothiazide, a
blocker of AMPA R (AMPA receptor) desensitization,
reduces TNFa release in combination with glutamate,
suggesting a feedback mechanism (Figure 3) [12]. Although
functional NMDA (N-methyl-D-aspartate) receptors have
not yet been described in microglia, transient forebrain
ischaemia results in the expression of the NR1 subunit of
the NMDA receptor and enhanced AMPA GluR4 subunit
expression in microglia, as revealed by immunohistochem-
istry [13]. It is important for us to determine whether this
expression is functional and whether it occurs in all acti-
vation paradigms for microglia.
www.sciencedirect.com
neurotoxicity and neuroprotection
Microglia express mGluRs, and stimulation by different
subtypes of mGluRs can transform microglia into a neu-
roprotective (via group III mGluRs) or neurotoxic (via
group II mGluRs) phenotype (Figure 3) [14–17]. The direct
activation of group II mGluRs, particularly mGluR2,
induces microglial stress (mitochondrial depolarization
and apoptosis) [15,18] and neurotoxicity [17]. The toxicity
of microglial mGluR2 stimulation involves the microglial
release of TNFa and FasL (Fas ligand), which trigger
neuronal caspase-3 activation via TNFR1 (also known as
p55) and Fas receptor, leading to neuronal death [17].
These data suggest that pathways resulting in group II
mGluR stimulation in microglia can be targeted to control
microglial neurotoxicity.
 Review TRENDS in Neurosciences Vol.30 No.10 529

Figure 2. The consequences of purinergic- and cannabinoid-receptor activation. Lines with arrowheads indicate stimulation, and dashed lines with blocked ends indicate
inhibition. LPS-induced IL-6 production can be inhibited by activation of the P2Y purinergic receptor [26]. LPS stimulation can induce the release of ATP in levels that cause
inhibition and/or desensitization of P2Y and P2X7 purinergic receptors. Stimulation with low ATP concentrations of P2Y receptors, particularly P2Y12, can, via inhibitory G-
protein Gi/Go-mediated pathways, induce membrane ruffling, chemotaxis and movement of fine microglial-cell processes [6,7,31,32] and the release of IL-6 and IL-12.
Stimulation of P2X7 receptors with higher ATP concentrations can lead to increased cytoplasmic calcium, the synthesis of the endocannabinoid 2-AG and subsequent
activation of the cannabinoid CB2 receptor, leading to proliferation [40,61]. In addition, P2X7 stimulation can induce the enhanced production of plasma-membrane-
produced SO [41] via activation of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase). High ATP concentrations can also lead to activation of the P2X4
receptor; this activation leads to BDNF synthesis via the activation of extracellular-signal-regulated kinase/p38 subgroups of mitogen-activated protein kinases (ERK/p38)
[90,91]. Stimulation of cannabinoid CB2 receptors increases proliferation [61] and migration [60]. Migration also increases after stimulation of the abn-CBD cannabinoid
receptor [60]. CB1 receptors have a predominantly cytoplasmic location [63] but can inhibit NO production [62], suggesting that they might translocate to the plasma
membrane under certain conditions. Microglial activation induced by exposure to fibrillar Ab1–40 is suppressed by the stimulation of CB2 receptors [68], as is LPS and
interferon gamma (IFNg)-induced microglial neurotoxicity [70].

Activation of microglia with amyloid b (Ab) peptides or
chromogranin A peptide (CgA), all expressed in Alzhei-
mer’s plaques, causes microglial glutamate release, result-
ing in a feedback activation of group II mGluRs on
microglia and fueling microglial neurotoxicity [15,19].
Activation of microglia with CgA, lipopolysaccharide
(LPS) or Ab peptides does not result in activation of group
III mGluRs [16,17], suggesting that insufficient glutamate
is released to activate this group of mGluRs. This concurs
with data from cloned mGluRs indicating that mGluR2
and mGluR3 respond to much lower glutamate concen-
trations than group III mGluRs [20]. Recent evidence also
suggests that group II mGluRs (as well as group I mGluRs)
can be activated by basal levels of glutamate [21]. The
neurotoxicity of microglia activated with CgA, LPS or by
direct mGluR2 stimulation can be prevented by agonists of
microglial group III mGluRs [16,17], suggesting that this
group of mGluRs offers further targets for controlling
microglial toxicity in neurodegenerative diseases. These
experiments show that the release of glutamate from
www.sciencedirect.com
microglia can lead to activation of mGluRs on these cells
in vitro, but dysregulation of glutamate handling in chronic
neurological conditions is also likely to influence signalling
cascades via these microglial receptors.
GABAB receptors modulate interleukin (IL) release
GABA (gamma-amino-butyric acid, also known as g-ami-
nobutyric acid) can act as a neuroprotective agent in
addition to playing a well-established role as the main
inhibitory neurotransmitter in the CNS. All three principle
GABAB receptors are expressed by microglia in situ and in
culture [22]. GABAB receptor stimulation leads to the
activation of a K+ conductance in cultured microglia and
in acute brain slices, and microglial activation leads to an
increase in the expression of GABAB receptors in the facial
axotomy model of microglial activation [22]. When cultured
microglia are activated with LPS, IL-6 and IL-12p40
release can be attenuated by GABAB receptor agonists,
indicating that GABA exerts an anti-inflammatory
response in microglia.
530 Review TRENDS in Neurosciences Vol.30 No.10

Figure 3. The consequences of glutamate-, GABA-, opioid-, adrenergic-, acetylcholine-, neurokinin- and adenosine-receptor activation. Lines with arrowheads indicate
stimulation, and dashed lines with blocked ends indicate inhibition. Stimulation of iGluRs modulates TNFa release [11,12], and GABAB agonists inhibit LPS-induced
interleukin-12 fragment p40 (IL-12p40) release [92]. LPS-induced TNFa release can be inhibited by agonists of the adenosine A3 receptor [47], by acetylcholine (ACh) or by
nicotine stimulation of the a7-nicotinamide ACh (a7nACh) receptor at the point of ERK/p38 phosphorylation [55]. LPS-induced IL-6 production can be inhibited by GABAB
agonists [92]. NK-1 stimulation by substance P induces enhanced production of plasma-membrane-produced SO via the activation of NADPH oxidase and stimulates
chemotaxis [83]. Stimulation of MORs, particularly MOR3, leads to PtdIns3K/Rac-mediated chemotaxis [72], BDNF expression and suppression of RANTES production.
Stimulation of KORs inhibits SO production [75], HIV-1 expression, HIV-1-p24-antigen production and quinolinate release [77,93]. Beta-2-adrenergic agonists promote
inhibition of LPS-induced IL-12p40 release [50], as well as inhibition of proliferation and activation-induced NO production from inducible nitric oxide synthase (iNOS)
activity [51]. Stimulation of the a7nAChR can curtail microglial activation induced by IFNg or HIV glycoprotein-120 (gp120) [55,57]. Stimulation of adenosine A2a receptor
can induce expression of COX-2 mRNA, synthesis of PGE2 and production of NGF. LPS, Ab25–35 or CgA-induced microglial activation can be inhibited by activation of group
III mGluRs [16]. The same microglial activators induce glutamate release from microglia, which binds onto group II mGluRs and leads to their activation and the subsequent
promotion of microglial-cell stress [15,19]. Direct stimulation of mGluR2 leads to TNFa release and FasL shedding [17], whereas stimulation of mGluR1 and mGluR5 leads to
increased cytoplasmic calcium [14].

Purinergic receptors control migration and cytokine
release
ATP induces a rapid microglial activation in response to
local brain injury in vivo [6], and microglia express a
variety of purinergic receptors (Table 1) [23–25]. Purinor-
eceptors control several properties of microglia, including
the motility of their fine processes, the release of cytokines,
migration and phagocytosis (Figure 2) [26–29]. ATP trig-
gers a rapid physiological response, the activation of
cationic and potassium conductance and an increase in
intracellular calcium (for a review, see [30]). Movement of
microglia is controlled by P2Y receptors, which induce
membrane ruffling and enhanced chemotaxis [31,29].
Recent data from direct imaging through the thinned skull
of a living mouse have revealed that local damage results
in a rapid attraction of the ramified processes of resting
microglia [6,7]. This movement can be mimicked by ATP
and is due to activation of the P2Y12 receptor [32]. This
receptor is only expressed in resting microglia in vivo and
in unstimulated cultured microglia; it is absent from per-
www.sciencedirect.com
ipheral macrophages [33,32]. After microglial activation by
stroke in vivo, or by LPS in culture, the P2Y12 receptor is
downregulated [32]. By contrast, P2Y12 mRNA is upregu-
lated in microglia in the facial nucleus after facial-nerve
axotomy, a classic model for microglial activation [33].
Moreover, in P2Y12-receptor-deficient animals the chemo-
tactic response to ATP is reduced but not absent, indicating
that one or more other receptors might additionally control
this behaviour [32].
Phagocytosis by microglia can be stimulated by UDP
acting at P2Y6 receptors [28]. These receptors are upregu-
lated when neurons are damaged, and they might act as
phagocytic sensors for diffusible UDP signals generated
after neuronal damage [28].
Purinergic receptors can control the release of cyto-
kines: ATP acting at P2Y receptors promotes the release
of ILs [34–36]. However, co-incubation of LPS with increas-
ing concentrations of ATP attenuates cytokine and chemo-
kine release from cultured microglia via P2Y receptors
[37,38], suggesting the presence of another feedback loop.
 Review TRENDS in Neurosciences Vol.30 No.10 531

Table 1. Expression of neurotransmitter receptors on microglia

Receptor Subtypes Functional activity Refs
Glutamate, ionotropic
AMPA mRNA flip variants of GluRs 1–4 GluR1 and GluR3 in flip form. [11]
mRNA flop variants of GluR2 and GluR4 Modulate TNFa release. [12]
NMDA NR1 subunit expressed after transient No functional activity shown so far. [13]
forebrain ischaemia
Glutamate, metabotropic
Group I mGluR1 and mGluR5a mRNA Agonist 1S,3R-ACPD induces increased Ca2+. [14]
Group II mGluR2 and mGluR3 mRNA and protein Activation of mGluR2 induces neurotoxic microglial phenotype and [15,17]
TNFa release.
Group III mGluR4, -6 and -8 (but not -7) mRNA and Activation is protective of microglia and neurones when microglia are [16]
protein exposed to activating stimuli.
Group II and III negatively coupled to adenylate cyclase. [15,16]
GABA
GABA(B), GABA(B1a), GABA(B1b) and Stimulation of GABAB leads to activation of a K+ conductance; attenuates [22]
GABA(B2) proteins LPS-induced interleukin release.
Purinergic
ATP Gi/Go-coupled P2Y (Y1, Y2, Y4 and Y12), Agonists cause a cationic conductance, increased K+ conductance and [23–25,
P2X (X1, X4, and X7), P2Y8 and increased intracellular Ca2+; membrane ruffling and chemotaxis. 29–31]
P2X6 mRNA and protein
P2Y12 Modulate movement of microglial fine processes. [6,32]
Activation induces chemotaxis. [29]
P2Y6 mRNA and receptor protein is upregulated on microglia after neuronal [28]
injury; functions as a mediator of microglial phagocytosis; responds to UDP.
P2X7 Triggers TNFa release. [27,39]
Controls endocannabinoid-2-arachidonylglycerol production; [40]
requires high ATP concentration.
Modulates superoxide production. [41,42]
P2X4 Activation implicated in neuropathic pain pathways. [42,43]
Activation induces chemotaxis. [29]
Adenosine
A2a Induces expression of NGF, COX-2 mRNA and synthesis of PGE2. [44,45]
A3 Suppresses LPS-induced TNFa release. [47]
Cholinergic
a7 nAChR subunit ACh or nicotine inhibits LPS-induced TNFa release. [55]
Nicotine attenuates gp120 or IFNg-induced microglia activation. [57]
Cannabinoid
CB2 receptor expressed in perivascular Activation reduces microglial toxicity and cytokine secretion. [79,94]
microglia Present on cultured microglia. [59,63]
CB1, CB2 and abn-CBD Non-specific activation of cannabinoid receptors suppresses microglial [60,61]
activation and neurotoxicity.
Stimulation of CB2 and abn-CBD increases cell migration. [66]
Stimulation of CB2 induces proliferation and blocks microglial activation [68]
induced by Ab1-40.
Adrenergic
mRNA for a1, a2, b1 and Agonists decrease mRNA for IL-6 and TNFa. [52,53]
b2 (but not b3) Functional noradrenergic receptors identified on cultured microglia and [48,95]
in acutely isolated brain slices; modulates membrane currents; suppresses
cytokine and NO release.
b-adrenergic agonist; isporoterenol; inhibits PMA-induced [49]
superoxide production.
b2 agonists inhibit LPS-induced IL-12p40 release and suppress proliferation. [50,51]
Dopamine
D1- and D2-like receptors, expression Functional dopamine receptors identified on cultured microglia and in [48]
inferred from function acutely isolated brain slices; modulates membrane currents; suppresses
NO release; promotes migration.
Opioid
MOR and KOR mRNA Evidence of MOR and KOR function and an opioid-receptor- [79,80]
independent pathway.
MOR MOR3 in cat and rat microglia Agonists induce ameboid phenotype in microglia, chemotaxis and [71,72]
BDNF-gene expression.
MOR mRNA constitutively expressed in Morphine inhibits C5a and RANTES chemotaxis and LPS- or IL1b-induced [73,74]
cultured human foetal microglia productionof RANTES.
KOR KOR agonists prevent cytokine- or PMA-induced superoxide production, [75,76,77]
HIV-related toxicity and quinolinate release from human foetal microglia.
Neuropeptide
Substance P neurokinin-1 (NK-1) Modulates chemotaxis; activates of NADPH oxidase. [81–83]
Bradykinin B1 and B2 Increases microglial motility; releases NO and PGE2 . [85,86]
PACAP or VIP VPAC1 Inhibits production of inflammatory chemokines and cytokines. [87,88]
Expression of neurotransmitters on microglia are shown in terms of the subtypes that have currently been identified by mRNA and protein expression, along with their
functional activity in microglia.
Abbreviations: abn-CBD, abnormal cannabidiol-sensitive receptor; C5a, protein fragment released from complement component C5; nAChR, nicotinic acetylcholinergic receptor.

www.sciencedirect.com
532 Review TRENDS in Neurosciences
Activation of the large-pore P2X7 receptor leads to
release of TNFa [39]. The P2X7 receptor is activated only
at higher ATP concentrations (above 1 mM) and stimulates
the production of the endocannabinoid-2-arachidonylgly-
cerol [40] and superoxide (O2*, or SO) production [41].
Recently, it has been shown that the tactile allodynia
induced by peripheral nerve injury can be reversed by the
blockade of spinal P2X4 ionotropic ATP receptors, which
are upregulated on microglia during injury [42]. This
suggests that P2X4 receptors on microglia might have
therapeutic potential for chronic neuropathic pain after
nerve injury, as well as for diseases, such as diabetes and
AIDS, that affect peripheral nerve function [42,43].
Adenosine receptors play a dual role
The neuroprotective effect of adenosine might be linked to
the release of neurotrophic factors, such as nerve growth
factor (NGF), via the activation of A2a receptors (Figure 3)
[44]. However, activation of microglial A2a receptors also
induces the expression of COX (cyclooxygenase)-2 mRNA,
the synthesis of prostaglandin E2 (PGE2) [45] and the
potentiation of nitric oxide (NO) release from activated
microglia. This suggests that the specific attenuation of
microglial A2a receptors might underlie the neuroprotec-
tive properties of A2a-receptor antagonists in several in
vivo models of neuronal death [46]. Furthermore, acti-
vation of microglial adenosine A3 receptors suppresses
LPS-induced production of TNF-a [47].
Adrenergic, dopmaninergic and cholinergic receptors
exhibit anti-inflammatory effects
Functional noradrenergic and dopaminergic receptors
modulate membrane currents in microglia in acutely iso-
lated brain slices [48]. Beta-adrenergic agonists inhibit
PMA (phorbol 12-myristate 13-acetate)-induced SO pro-
duction [49] and LPS-induced IL-12p40 release [50] and
suppress microglial proliferation (Figure 3) [51]. Stimu-
lation of adrenergic receptors decreases cytokine and NO
expression and release [48,52,53]. Chronic application of
dopamine also attenuates LPS-induced NO release but not
TNFa and IL-6a release, indicating that the two types of
aminergic receptors are linked to distinct signalling path-
ways [48].
Cortical microglial inflammatory responses are
increased when noradrenaline levels are depleted,
suggesting that noradrenaline could reduce microglial acti-
vation, and loss of noradrenergic neurons augments micro-
glial inflammatory responses [54]. This has implications for
a loss of control of microglial reactivity in Alzheimer’s dis-
ease and Parkinson’s disease, both of which display loss
of locus ceruleus (LC) neurones, loss of noradrenergic pro-
jections and decreased cortical noradrenergic levels,
together with enhanced activation of microglia.
So far, there are few reports concerning cholinergic
receptors on microglia, but activation appears to promote
anti-inflammatory and neuroprotective responses. Cul-
tured murine microglia express the a7 nicotinic-acetyl-
choline-receptor subunit [55,56]. Acetylcholine or
nicotine inhibits microglial activation induced by LPS,
IFN-gamma or the human immunodeficiency virus type
1 (HIV-1) coat glycoprotein gp120 but also enhances the
www.sciencedirect.com
Vol.30 No.10
expression of cyclooxygenease-2 and the synthesis of PGE2.
Because the latter might modulate microglial inflamma-
tory responses, overall, the activation of ACh receptors on
microglia might be neuroprotective [55–58]. Therefore, loss
of cholinergic neurones in progressive neurodegenerative
diseases might lead to an increased susceptibility for
microglia to become progressively activated [55]. This
microglial pathway could also be a therapeutic target for
treating HIV-associated dementia [57].
Cannabinoid receptors mediate neuroprotection
Activated microglia express CB2 cannabinoid receptors
when their expression in the normal brain is very low
(for a review, see [59]). Activation of the microglial CB2
receptor stimulates microglial migration [60] and prolifer-
ation [61], and the receptor works in concert with the
abnormal-cannabidiol-sensitive receptor to modulate
microglial migration (Figure 2) [60]. Activation of CB1
mediates inhibition of NO production by rat microglia
[62], although the proposed intracellular location of CB1
receptors on microglia [63] indicates that receptor intern-
alization can occur as a mechanism of receptor downregu-
lation. LPS-induced cytokine expression and release in
microglia can be inhibited by cannabinoid-receptor ago-
nists [64,65]; this implies an anti-inflammatory role of
cannabinoids and a role in neuroprotection. Moreover, in
LPS-stimulated cultured microglia, the selective ananda-
mide-uptake inhibitor UCM707 decreases the production
of proinflammatory cytokines and NO generation [66]. The
suppressive effect of cannabinoid-receptor stimulation on
microglial activation is supported by the finding that ana-
ndamide attenuates the inflammation and neurotoxicity of
microglia added to organotypic hippocampal-slice culture
models of neuronal injury by modulating microglial
MAPK-signal-transduction cascades [67].
Furthermore, in a multiple-sclerosis model, Theiler’s
murine encephalomyelitis virus (TMEV)-induced demye-
linating disease, UCM707 reduced microglial activation
and diminished major histocompatibility complex class-II-
antigen expression. Ramirez et al. [68] found CB2 receptors
together with markers of microglial activation in senile
plaques of patients with Alzheimer’s disease. In vitro,
stimulation of the microglial CB2 receptor blocks micro-
glial activation induced by fibrillar Ab1–40 [68], and, if
microglial activation plays a negative role in the pro-
gression of Alzheimer’s disease, microglia are likely to
be important targets for cannabinoids used as therapeutic
agents [69]. In line with this, stimulation of microglial CB2
receptors can reduce the subsequent neurotoxicity of acti-
vated microglia [70].
Opioid receptors on microglia and their involvement in
Parkinsońs disease, Alzheimeŕs disease and HIV
dementia
Of the three classes of opioid receptors (delta [d], mu [m]
and kappa [k]) so far identified, microglia express m-opioid
receptors (MORs) and k-opioid receptors (KORs) but not d
receptors, and they also express a third, seemingly opioid-
receptor-independent pathway for the activity of endogen-
ous opioid-receptor ligands, such as dynophin. MOR3 acti-
vation triggers morphological changes and brain-derived
 Review TRENDS in Neurosciences
neurotrophic factor (BDNF) expression [71,72] and inhibits
microglial chemotaxis and migration, indicating an anti-
inflammatory role of MOR in microglia (Figure 3) [73,74].
Morphine also inhibits RANTES (regulated upon acti-
vation, normal T-cell expressed and secreted chemokine)
production by activated microglia [74] and triggers micro-
glial apoptosis [75].
Microglial KORs exert an anti-inflammatory effect
because selective KOR agonists attenuate the production
of SO anion from activated human foetal-derived microglia
[75]. Microglia are the sink-cell for the reproduction and
shedding of HIV-1 [76]. KOR agonists inhibit HIV-1
expression, HIV-1 p24-antigen production, release of qui-
nolinate and subsequent neurotoxicity in acutely infected
microglial-cell cultures [77]. Thus, pathways in microglia
activated by KORs might have therapeutic potential in
HIV-1 encephalopathy. Interestingly, pretreatment of
microglia with KOR agonists can also abrogate a
cocaine-induced potentiation of HIV-1 expression by blunt-
ing cocaine-enhanced upregulation of HIV-1 entry via the
chemokine coreceptor CCR5 [78].
There is emerging evidence that microglia might pos-
sess opioid non-receptor-mediated pathways that can
influence microglial reactivity and that can be activated
by N-truncated fragments of dynophin A (dyn2–17) or inac-
tive isomers of naloxone [79,80]. When injected into rats,
dyn2–17 selectively induces p38 activation and the release
of p38-dependent PGE2 mediated by COX-1 and COX-2 in
microglia; therefore, dyn2–17 could contribute to dynor-
phin-evoked spinal sensitization and hyperalgesia [80].
Although this suggests that activation of non-opioid recep-
tors in spinal-cord microglia might be detrimental, acti-
vation of this non-opioid-receptor pathway in other areas of
the brain might be beneficial. Thus, attenuation of inflam-
mation-mediated (via LPS or Ab1–42) degeneration of dopa-
minergic neurones can be achieved by inhibiting the
activation of microglia with dyn2–17 or (+)-naloxone (the
ineffective enantiomer of ()-naloxone) but not with
U50488, a synthetic KOR agonist [79]. Furthermore, pre-
treatment of neuron-glial cultures with either naloxone
stereoisomer before exposure to Ab1–42 can provide signifi-
cant neuroprotection by inhibiting SO production in micro-
glia [79]. Thus, on the one hand, naloxone analogues,
especially (+)-naloxone, might have therapeutic potential
for the treatment of Alzheimer’s and Parkinson’s diseases
[79], but on the other hand, the pronociceptive effects of
both dyn1–17 and dyn2–17, as well as that of naloxone, would
require suppression if targeting this receptor pathway
were to become a feasible therapeutic strategy for pro-
gressive neurodegenerative diseases, such as Alzheimer’s
and Parkinson’s diseases.
Neuropeptides can be pro- and anti-inflammatory
Evidence suggests that the tachykinin substance P aug-
ments proinflammatory responses in microglia. Microglia
can express substance P [81] and its receptor, neurokinin-1
(NK-1), suggesting an autocrine loop for substance P sig-
nalling in microglia. Substance P can stimulate chemotaxis
at low concentrations of only 10 nM via an NK-1-mediated
pathway and activate the transcriptional factor NF-kB
[82] and microglial NADPH oxidase; the activation of
www.sciencedirect.com
Vol.30 No.10 533
microglial NADPH leads to the generation of extracellular
SO, intracellular ROS and microglial-evoked neurotoxicity
of dopaminergic neurons [83]. In a model of Lyme disease,
substance P can augment expression of PGE2 receptors
and E-prostanoid-receptor subtypes 2 and 4 [84].
The nonapeptide bradykinin (BK) is widespread in var-
ious tissues, including brain tissue, and is a known inflam-
matory mediator. The B1 BK receptor is upregulated and
the B2 receptor downregulated in microglia in response to
BK itself [85], whereas in unstimulated microglia, B2 but
not B1 receptors are expressed. BK receptors in microglia
are linked to Ins(1,4,5)P3 signalling, leading to increased
intracellular calcium and activation of Ca2+-dependent K+
channels via Gq/11 signalling [86]. BK increases microglial
motility and induces the release of NO and PGE2 [86], but
it can also reduce LPS-induced release of TNFa and IL-1b,
possibly by an autocrine feedback loop via PGE2-induced
formation of cAMP [86].
Pituitary-adenylate-cyclase-activating polypeptide
(PACAP) and vasoactive intestinal peptide (VIP) can inhi-
bit the production of inflammatory cytokines and chemo-
kines from microglia and have significant potential for the
treatment of acute and chronic neurological conditions,
such as ischaemia, multiple sclerosis and Parkinson’s dis-
ease, in which inflammation-induced neurodegeneration
occurs [87,88]. VIP and PACAP inhibit JAK1–2 and STAT1
phosphorylation to control gene expression of IFN-gamma-
inducible protein-10 (IP-10), CD40 and iNOS via the
specific VPAC1 receptor and the cAMP/protein-kinase-A
transduction pathway [88]. Thus, different neuropeptides
can have pro- or anti-inflammatory actions in microglia.
Given that there are at least 100 currently known neuro-
peptides in the brain, this represents a vast unexplored
area for microglial signalling and is likely to offer rich
potential for therapeutic exploitation.
Conclusion
It is evident that microglia express a variety of neuro-
transmitter receptors and that these receptors control
microglial functions. One could speculate that, during
normal brain function, extrasynaptic neurotransmitters
signal to microglia that neurons are active and thereby
suppress microglial activation. Essentially, all the known
functions of microglia are linked to pathology, and this
implies that neurotransmitters can influence pathologic
processes via microglia. One of the major handicaps in
studying microglia is their rapid activation and transform-
ation after any change in their environment. This implies
that any manipulation, such as isolation from brain tissue
or culturing procedures, will transform them into an acti-
vated stage. Because the bulk of our literature is based on
studies of cultured microglia, we know next to nothing
about the function of resting microglia. Therefore, one of
the big challenges of future research will be the study of
their function in a tissue context or, even better, in a living
animal. It is also evident that several questions remain
open. Although we know that neurons form a heterogenous
cell population, we do not know whether microglia differ
from one brain region to the next or whether they are
heterogenous even within one brain area. The changes
in receptor expression at various stages of microglial
534 Review TRENDS in Neurosciences
activation are just being elucidated. Furthermore, as has
been shown for neurones, the subcellular location of these
different receptors on microglia is not known. Although
considerable data exist on the functional plasticity of
microglia in terms of their morphological transformation,
little attention has been shown to the plasticity of expres-
sion of neurotransmitter receptors on microglia. The chal-
lenge ahead for researchers is (i) to dissect out the
signalling pathways coupled to different microglial recep-
tors and (ii) to determine the most suitable receptors for
therapeutic intervention in different neurodegenerative
diseases so that the protective properties of microglia
can be emphasized at the expense of their neurotoxicity.
References
1 Mittelbronn, M. et al. (2001) Local distribution of microglia in the
normal adult human central nervous system differs by up to one order
of magnitude. Acta. Neuropathol. (Berl.). 101, 249–255
2 del Rı́o-Hortega, P. (1919) El tercer elemento de los centros nerviosos.
Bol. Soc. Esp. Biol. 9, 69–120
3 van Rossum, D. and Hanisch, U.K. (2004) Microglia. Metab. Brain Dis.
19, 393–411
4 Kim, S.U. and De Vellis, J. (2005) Microglia in health and disease. J.
Neurosci. Res. 81, 302–313
5 Streit, J.W. (2002) Microglia as neuroprotective, immunocompetent
cells of the CNS. Glia 40, 133–139
6 Davalos, D. et al. (2005) ATP mediates rapid microglial responses to
local brain injury in vivo. Nat. Neurosci. 8, 752–758
7 Nimmerjahn, A. et al. (2005) Resting microglial cells are highly
dynamic surveillants of brain parenchyma in vivo. Science 308,
1314–1318
8 Lin, S.C. and Bergles, D.E. (2004) Synaptic signaling between neurons
and glia. Glia 47, 290–298
9 Agnati, L.F. et al. (1995) Intercellular communication in the brain:
wiring versus volume transmission. Neurosci. 69, 711–726
10 Zoli, M. et al. (1999) Volume transmission in the CNS and its relevance
for neuropsychopharmacology. Trends Pharmacol. Sci. 20, 142–150
11 Noda, M. et al. (2000) AMPA-kainate subtype of glutamate receptor in
rat cerebral microglia. J. Neurosci. 20, 251–258
12 Hagino, Y. et al. (2004) Heterogeneity and potentiation of AMPA type of
glutamate receptors in rat cultured microglia. Glia 47, 68–77
13 Gottlieb, M. and Matute, C. (1997) Expression of ionotropic glutamate
receptor subunits in glial cells of the hippocampal CA1 area following
transient forebrain ischaemia. J. Cereb. Blood Flow Metab. 17, 290–
300
14 Biber, K. et al. (1999) Expression and signalling of group I metabotropic
glutamate receptors in astrocytes and microglia. J. Neurochem. 72,
1671–1680
15 Taylor, D.L. et al. (2002) Activation of group II metabotropic glutamate
receptors underlies microglial reactivity and neurotoxicity following
stimulation with chromogranin A, a peptide up-regulated in
Alzheimer’s disease. J. Neurochem. 82, 1179–1191
16 Taylor, D.L. et al. (2003) Activation of microglial group III metabotropic
glutamate receptors protects neurons against microglial neurotoxicity.
J. Neurosci. 15, 2150–2160
17 Taylor, D.L. et al. (2005) Stimulation of microglial metabotopic
glutamate receptor, mGlu2 triggers TNFa-induced neurotoxicity in
concert with microglial derived FasL. J. Neurosci. 25, 2952–2964
18 Kingham, P.J. and Pocock, J.M. (2000) Microglial apoptosis induced by
chromogranin A is mediated by a mitochondrial depolarisation and the
permeability transition but not by cytochrome c release. J. Neurochem.
74, 1452–1462
19 Kingham, P.J. et al. (1999) Apoptotic pathways mobilized in microglia
and neurones as a consequence of chromogranin A-induced microglial
activation. J. Neurochem. 73, 538–547
20 Pin, J.P. and Duvoisin, R. (1995) The metabotropic glutamate
receptors: structure and functions. Neurosci. Lett. 133, 159–162
21 Bandrowski, A.E. et al. (2003) Baseline glutamate levels affect group I
and II mGluRs in layer V pyramidal neurons of rat sensorimotor cortex.
J. Neurophysiol. 89, 1308–1316
www.sciencedirect.com
Vol.30 No.10
22 Kuhn, S.A. et al. (2004) Microglia express GABAB receptors to
modulate interleukin release. Mol. Cell. Neurosci. 25, 312–322
23 Norenberg, W. et al. (1994) Characterisation and possible function of
adenosine 50 -triphosphate receptors in activated rat microglia. Br. J.
Pharmacol. 111, 942–950
24 James, G. and Butt, A.M. (2002) P2Y and P2X purinoceptor mediated
Ca2+ signalling in glial cell pathology in the central nervous system.
Eur. J. Pharmacol. 447, 247–260
25 Bianco, F. et al. (2005) Pathophysiological roles of extracellular
nucelotides in glial cells; differential expression of purinergic receptors
in resting and activated microglia. Brain Res. Brain Res. Rev. 48, 144–156
26 Ferrari, D. et al. (1997) ATP-mediated cytotoxicity in microglial cells.
Neuropharm. 36, 1295–1301
27 Hide, I. et al. (2000) Extracellular ATP triggers tumor necrosis factor-
alpha release from rat microglia. J. Neurochem. 75, 965–972
28 Koizumi, S. et al. (2007) UDP acting at P2Y6 receptors is a mediator of
microglial phagocytosis. Nature 446, 987–989
29 Ohsawa, K. et al. (2007) Involvement of P2X4 and P2Y12 receptors in
APT-induced microglial chemotaxis. Glia 55, 604–616
30 Färber, K. and Kettenmann, H. (2006) Purinergic signalling and
microglia. Pflugers Arch. Eur. J. Physiol 452, 615–621
31 Honda, S. et al. (2001) Extracellular ATP or ADP induced chemotaxis of
cultured microglia through Gi/o-coupled P2Y receptors. J. Neurosci. 21,
1975–1982
32 Haynes, S.E. et al. (2006) The P2Y12 receptor regulates microglial
activation by extracellular nucleotides. Nat. Neurosci. 9, 1512–1519
33 Sasaki, Y. et al. (2003) Selective expression of Gi/o-coupled ATP
receptor P2Y12 in microglia in rat brain. Glia 44, 242–250
34 Sanz, J.M. and Di Virgilio, F. (2000) Kinetics and mechanism of
ATP-dependent IL-1b release from microglia cells. J. Immunol. 164,
4893–4898
35 Shigemoto-Mogami, Y. et al. (2001) Mechanisms underlying ATP-
evoked interleukin-6 release in mouse microlgial cell line, MG-5. J.
Neurochem. 78, 1339–1349
36 Seo, D.R. et al. (2004) Interleukin-10 expression in lipopolysaccharide-
activated microglia is mediated by extracellular ATP in an autocrine
fashion. Neuroreport 15, 1157–1161
37 Boucsein, C. et al. (2003) Purinergic receptors on microglial cells:
functional expression in acute brain slices and modulation of
microglial activation in vitro. Eur. J. Neurosci. 17, 2267–2276
38 Ogata, T. et al. (2003) Adenosine triphosphate inhibits cytokine release
from lipopolysaccharide-activated microglia via P2Y receptors. Brain
Res. 981, 174–183
39 Suzuki, T. et al. (2004) Production and release of neuroprotective tumor
necrosis factor by P2X7 receptor-activated microglia. J. Neurosci. 24,
1–7
40 Witting, A. et al. (2004) P2X7 receptors control 2-arachidonoylglycerol
production by microglial cells. Proc. Natl. Acad. Sci. U. S. A. 101, 3214–
3219
41 Parvathenani, L.K. et al. (2003) P2X7 mediates superoxide production
in primary microglia and is upregulated in a transgenic mouse model of
Alzheimer‘s disease. J. Biol. Chem. 278, 13309–13317
42 Tsuda, M. et al. (2003) P2X4 receptors induced in spinal microglia gate
tactile allodynia after nerve injury. Nature 424, 778–783
43 Inoue, K. et al. (2006) The function of microglia through purinergic
receptors; Neuropathic pain and cytokine release. Pharmacol. Ther.
109, 210–226
44 Heese, K. et al. (1997) Nerve growth factor (NGF) expression in rat
microglia is induced by adenosine A2a-receptors. Neurosci. Lett. 231,
83–86
45 Fiebich, B.L. et al. (1996) Cyclooxygenase-2 expression in rat microglia
is induced by adenosine A2a-receptors. Glia 18, 152–160
46 Saura, J. et al. (2005) Adenosine A2A receptor stimulation potentiates
nitric oxide release by activated microglia. J. Neurochem. 95, 919–929
47 Lee, J.Y. et al. (2006) Activation of adenosine A(3) receptor suppresses
lipopolysaccharide-induced TNF-alpha production through inhibition
of PI13-kinase/Akt and NfkappaB activation in murine BV2 microglial
cells. Neurosci. Lett. 396, 1–6
48 Färber, K. et al. (2005) Dopamine and noradrenaline control distinct
functions in rodent microglial cells. Mol. Cell. Neurosci. 29, 128–138
49 Colton, C.A. and Chernyshev, O.N. (1996) Inhibition of microglial
superoxide anion production by isoproterenol and dexamethasone.
Neurochem. Int. 29, 43–53
 Review TRENDS in Neurosciences
50 Prinz, M. et al. (2001) b-adrenergic receptor stimulation selectively
inhibits IL-12p40 release in microglia. Brain Res. 899, 264–270
51 Fujita, H. et al. (1998) Adrenergic agonists suppress the proliferation
of microglia through b2-adrenergic receptor. Neurosci. Lett. 242, 37–40
52 Mori, K. et al. (2002) Effects of norepinephrine on rat cultured
microglial cells that express a1, a2, b1 and b2 adrenergic receptors.
Neuropharm. 43, 1026–1034
53 Tanaka, K.F. et al. (2002) Existence of functional b1 and b2 adrenergic
receptors on microglia. J. Neurosci. Res. 70, 232–237
54 Heneka, M.T. et al. (2002) Noradrenergic depletion potentiates beta-
amyloid-induced cortical inflammation: implications for Alzheimer’s
disease. J. Neurosci. 22, 2434–2442
55 Shytle, R.D. et al. (2004) Cholinergic modulation of microglial
activation by alpha 7 nicotinic receptors. J. Neurochem. 89, 337–
343
56 De Simone, R. et al. (2005) Activation of alpha7 nicotinic acetylcholine
receptor by nicotine selectively up-regulates cyclooxygenase-2 and
prostaglandin E2 in rat microglial cultures. J. Neuroinflammation 2, 4
57 Giunta, B. et al. (2004) Galantamine and nicotine have a synergistic
effect on inhibition of microglial activation induced by HIV-1 gp120.
Brain Res. Bull. 64, 165–170
58 Suzuki, T. et al. (2006) Microglial alpha7 nicotinic acetylcholine
receptors drive a phospholipase C/IP3 pathway and modulate the
cell actiation toward a neuroprotective role. J. Neurosci. Res. 83,
1451–1470
59 Stella, N. (2004) Cannabinoid signalling in glial cells. Glia 48, 267–277
60 Franklin, A. and Stella, N. (2003) Arachidonylcyclopropylamide
increases microglial cell migration through cannabinoid CB2 and
abnormal-cannabidiol-sensitive receptors. Eur. J. Pharmacol. 474,
195–198
61 Carrier, E.J. et al. (2004) Cultured rat microglial cells synthesize the
endocannabinoid 2-arachidonylglycerol which increases proliferation
via a CB2 receptor-dependent mechanism. Mol. Pharmacol. 65, 999–
1007
62 Waksman, Y. et al. (1999) The central cannabinoid receptor (CB1)
mediates inhibition of nitric oxide production by rat microglial cells.
J. Pharmacol. Exp. Ther. 288, 1357–1366
63 Walter, L. et al. (2003) Nonpsychotropic cannabinoid receptors
regulate microglial migration. J. Neurosci. 23, 1398–1405
64 Puffenbarger, R.A. et al. (2000) Cannabinoids inhibit LPS-inducible
cytokine mRNA expression in rat microglial cells. Glia 29, 58–69
65 Facchinetti, F. et al. (2003) Cannabinoids ablate release of TNF-alpha
in rat microglial cells stimulated with lippolysaccharide. Glia 41,
161–168
66 Ortega-Gutierrez, S. et al. (2005) Activation of the endocannabinoid
system as a therapeutic approach in a murine model of multiple
sclerosis. FASEB 19, 1338–1340
67 Eljaschewitsch, E. et al. (2006) The endocannabinoid anandamide
protects neurons during CNS inflammation by induction of MKP-1
in microglial cells. Neuron 49, 67–79
68 Ramirez, B.G. et al. (2005) Prevention of Alzheimer’s disease pathology
by cannabinoids; neuroprotection mediated by blockade of microglial
activation. J. Neurosci. 25, 1904–1913
69 Cabral, G.A. and Marciano-Cabral, F. (2005) Cannabinoid receptors in
microglia of the central nervous system: immune functional relevance.
J. Leukoc. Biol. 78, 1192–1197
70 Klegeris, A. et al. (2003) Reduction of human monocytic cell
neurotoxicity and cytokine secretion by ligands of the cannabinoid-
type CB2 receptor. Br. J. Pharmacol. 139, 775–786
71 Dobrenis, K. et al. (1995) Occurrence of the opiate alkaloid-selective
mu3 receptor in mammalian microglia, astrocytes and Kupffer cells.
Brain Res. 686, 239–248
Reproduction of material from Elsevier articles
Interested in reproducing part or all of an article published by Elsevier, or one of our article figures?
If so, please contact our Global Rights Department with details of how and where the requested
material will be used. To submit a permission request online, please visit:
www.elsevier.com/locate/permissions
www.sciencedirect.com
View publication stats
Vol.30 No.10 535
72 Takayama, N. and Ueda, H. (2005) Morphine-induced chemotaxis and
brain-derived neurotrophic factor expression in microglia. J. Neurosci.
25, 430–435
73 Chao, C.C. et al. (1997) Activation of mu opioid receptors inhibits
microglial cell chemotaxis. J. Pharmaco. Exp. Ther 281, 998–1004
74 Hu, S. et al. (2000) Morphine inhibits human microglial cell production
of, and migration towards, RANTES. J. Psychopharmacol. 14, 238–243
75 Hu, S. et al. (2002) Morphine induces apoptosis of human microglia and
neurons. Neuropharmacol. 42, 829–836
76 Wallace, D.R. (2006) HIV neurotoxicity: potential therapeutic
interventions. J. Biomed. Biotechnol. 2006, 65741–65751
77 Chao, C.C. et al. (2000) U50488 protection against HIV-1-related
neurotoxicity: involvement of quinolinic acid suppression.
Neuropharmacol. 39, 150–160
78 Gekker, G. et al. (2004) Kappa-opioid receptor ligands inhibit cocaine-
induced HIV-1 expression in microglial cells. J. Pharmacol. Exp. Ther.
309, 600–606
79 Liu, Y. et al. (2002) Inhibition by naloxone stereoisomers of beta-
amyloid peptide (1-42)-induced superoxide production in microglia
and degeneration of cortical and mesencephalic neurons. J.
Pharmacol. Exp. Ther. 302, 1212–1219
80 Svensson, C.I. et al. (2005) Prostaglandin E2 release evoked by
intrathecal dynorphin is dependent on spinal p38 mitogen activated
protein kinase. Neuropeptides 39, 485–494
81 Lai, J.P. et al. (2000) Detection of substance P and its receptor in
human fetal microglia. Neurosci. 101, 1137–1144
82 Rasley, A. et al. (2002) Expression of functional NK-1 receptors in
murine microglia. Glia 37, 258–267
83 Block, M.L. et al. (2006) Potent regulation of microglial-derived
oxidative stress and dopaminergic neuron survival: substance P vs
dynorphin. FASEB J. 20, 251–258
84 Rasley, A. et al. (2004) Substance P augments Borrelia burgdorferi-
induced prostaglandin E2 production by murine microglia. J.
Immunol. 172, 5707–5713
85 Noda, M. et al. (2003) Expression and function of bradykinin receptors
in microglia. Life Sci. 72, 1573–1581
86 Noda, M. et al. (2006) Anti-inflammatory effects of kinins via microglia
in the central nervous system. Biol. Chem. 51, 167–171
87 Dejda, A. et al. (2005) Neuroprotective potential of three neuropeptides
PACAP, VIP and PHI. Pharmacol. Rep. 57, 307–320
88 Gonzalez-Rey, E. and Delgado, M. (2005) Role of vasoactive intestinal
peptide in inflammation and autoimmunity. Curr. Opin. Invest. Drugs.
6, 1116–1123
89 Boucsein, C. et al. (2000) Electrophysiological properties of microglial
cells in normal and pathologic rat brain slices. Eur. J. Neurosci. 12,
2049–2058
90 Tsuda, M. et al. (2004) Activation of p38 mitogen-activated protein
kinase in spinal hyperactive microglia contributes to pain
hypersensitivity following peripheral nerve injury. Glia 45, 89–95
91 Coull, J.A. et al. (2005) BDNF from microglia causes the shift in neuronal
anion gradient underlying neuropathic pain. Nature 438, 1017–1021
92 Charles, K.J. et al. (2003) GABA B receptor subunit expression in glia.
Mol. Cell. Neurosci. 24, 214–223
93 Chao, C.C. et al. (1996) kappa opioid receptors in human microglia
downregulate human immunodeficiency virus 1 expression. Proc. Natl
Acad. Sci. U. S. A. 93, 8051–8056
94 Nuñez, E. et al. (2004) Cannabinoid CB2 receptors are expressed
by perivascular microglial cells in the human brain: an
immunohistochemical study. Synapse 15, 208–213
95 Dello Russo, C. et al. (2004) Inhibition of microglial inflammatory
responses by norepinephrine: effects on nitric oxide and interleukin-
1beta production. J. Neuroinflammation 1, 9