1. Are chemokines the third major system in the brain?
Martin W. Adler*,†,1 and Thomas J. Rogers*,†,‡
*Center for Substance Abuse Research, ‡Fels Institute for Cancer Research and Molecular Biology,
†Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania
Abstract: Chemokines are a family of small pro-teins
involved in cellular migration and intercellu-lar
communication. Although the chemokines and
their receptors are located throughout the brain,
they are not distributed uniformly. Among the che-mokines
and their receptors that are arrayed dis-proportionately
in glia and neurons are monocyte
chemotactic protein-1/CC chemokine ligand 2
(CCL2), stromal cell-derived factor-1/CXC chemo-kine
ligand 12 (CXCL12), fractalkine/CX3C che-mokine
ligand 1, interferon--inducible-protein-
10/CXCL10, macrophage inflammatory protein-
1/CCL3, and regulated on activation, normal T
cell expressed and secreted/CCL5. In the brain,
they are found in the hypothalamus, nucleus ac-cumbens,
limbic system, hippocampus, thalamus,
cortex, and cerebellum. The uneven distribution
suggests that there may be functional roles for the
chemokine “system,” comprised of chemokine li-gands
and their receptors. In addition to anatomi-cal,
immunohistochemical, and in vitro studies es-tablishing
the expression of the chemokine ligands
and receptors, there is an increasing body of re-search
that suggests that the chemokine system
plays a crucial role in brain development and func-tion.
Our data indicate that the chemokine system
can alter the actions of neuronally active pharma-cological
agents including the opioids and cannabi-noids.
Combined with evidence that the chemokine
system in the brain interacts with neurotransmitter
systems, we propose the following hypothesis: The
endogenous chemokine system in the brain acts in
concert with the neurotransmitter and neuropep-tide
systems to govern brain function. The chemo-kine
system can thus be thought of as the third
major transmitter system in the brain. J. Leukoc.
Biol. 78: 1204–1209; 2005.
Key Words: opioids heterologous desensitization neuromodula-tors
interneuronal communication
INTRODUCTION
Chemokines are a family of small (8–12 kDa) proteins involved
in cellular migration and intercellular communication, and
their receptors are members of the G protein-coupled receptor
(GPCR) superfamily. Most chemokines act on more than one
receptor, although a few, such as CXC chemokine ligand 12
(CXCL12) and CX3C chemokine ligand 1 (CX3CL1) appear to
act on only one [1, 2]. Although it appears that some chemo-kines
and their receptors are expressed by glia and neurons
throughout the brain, others, such as CC chemokine ligand 2
(CCL2), CCL3, CCL5, CXCL10, CXCL12, and CX3CL1, are
not distributed uniformly [3, 4]. Such uneven distribution is
characteristic of the neurotransmitter and neuropeptide sys-tems
and may hold a clue as to possible functional roles played
by the different members of these systems in certain defined
brain regions. Chemokines and their receptors are found in
microglia and neurons in such brain areas as the hypothala-mus,
nucleus accumbens, limbic system, hippocampus, thala-mus,
cortex, and cerebellum [3– 6]. Neural progenitor cells and
mature neurons express multiple functional chemokine recep-tors
and chemokines [7, 8]. In addition, small numbers of
resident immune cells are present in the brain [9, 10] and are
likely to contribute chemokine ligands to the brain tissue.
DEFINITIONS
A number of terms and classifications have been used in an
attempt to categorize neuroactive compounds, chemicals that
affect neuronal activity and play a functional role in regulating
activity of the brain in normal, pathological, and homeostatic
states. Among the most commonly used terms are neurotrans-mitter,
neuromodulator, and neurohormone. Neuropeptides are
often considered separately, and neurohormones (e.g., hypo-thalamic-
releasing factors) are a type of neuropeptide. Some
characteristics of these categories are summarized in Table 1
[11].
The terms neurotransmitter, neuromodulator, and neurohor-mone
are not precise; indeed, the different terms can be
applied to the same chemical at different sites of action [11].
For example, dopamine is a neurotransmitter in the striatum
but is a neurohormone to the pituitary. In addition, serotonin is
a neurotransmitter in raphe nuclei but is a neuromodulator at
the facial motor nucleus. Finally, most neuropeptides are neu-romodulators,
but substance P is a neurotransmitter at sensory
afferents to the dorsal horn in the spinal cord.
Irrespective of terminology such as that cited above, neuro-scientists
generally think of the systems of chemicals classified
1 Correspondence: Center for Substance Abuse Research, Temple Univer-sity
School of Medicine, 3400 N. Broad Street, Philadelphia, PA 19140.
E-mail: baldeagl@temple.edu
Received April 24, 2005; revised August 26, 2005; accepted September 9,
2005; doi: 10.1189/jlb.0405222.
1204 Journal of Leukocyte Biology Volume 78, December 2005 0741-5400/05/0078-1204 © Society for Leukocyte Biology

2. TABLE 1. Characteristics of Major Neuroactive Compounds
Compound Characteristics
Neurotransmitter Endogenous chemicals that are synthesized and released presynaptically following nerve stimulation. They potentiate
or block postsynaptic responses (e.g., serotonin, dopamine, acetylcholine), and they are stored in a form ready to
be released. There must also be mechanisms for inactivation or for removal from the synaptic cleft.
Neuromodulators Compounds that have no intrinsic activity but can modify synaptic activity, modulate transmission, and involve a
second messenger system (most neuropeptides).
Neurohormones Compounds have intrinsic activity, are released from neuronal and non-neuronal cells, and can travel and act at a
site distant from their release site (e.g., -endorphin).
Neuropeptides Small proteins that target specific cells in the nervous system, including neurons and glia. Precursors are
synthesized in the neuronal cell body [e.g., pro-opiomelanocortin for -endorphin and adrenocorticotropin
(ACTH)]. The mechanisms for inactivation in the synaptic cleft are not yet known for all members of the group.
as neurotransmitters (e.g., acetylcholine, norepinephrine, do-pamine,
serotonin, -aminobutyric acid) or neuropeptides (e.g.,
-endorphin, enkephalins, dynorphin, cholecystokinin, sub-stance
P, endocannabinoids, somatostatin) as being responsi-ble
for neuronal transmission or modulation of neuronal events.
The molar concentration of neuropeptides is two or three orders
of magnitude lower than neurotransmitters, and their receptors
respond to the lower concentrations. Neurotransmitters and
neuropeptides may be co-localized in individual synaptic ter-minals
and may be co-released. Like the neurotransmitter and
neuropeptide systems, the chemokine system, composed of
chemokine ligands and their respective receptors, is widely but
unevenly distributed in the brain and has ligands and receptors
located in neurons. Neurotransmitter and neuropeptide sys-tems
interact in the brain, and it is therefore logical to postu-late
that the chemokine system interacts functionally with both
of these other neuronal systems.
HETEROLOGOUS DESENSITIZATION
Most reports on the subject of chemokines and their receptors
in the brain have focused on their role in inflammatory pro-cesses
or neurogenesis. The possibility that these substances
play an even more fundamental role in neurotransmission has
not been given adequate consideration. Work carried out with
leukocytes in vitro first showed that opioid treatment sup-pressed
chemokine-mediated chemotactic responses, and this
was shown to be a result of (at least in part) the process of
heterologous desensitization between opioids and some of the
chemokine receptors (Fig. 1) [12]. Subsequently, results were
reported that demonstrated that the heterologous desensitiza-tion
process is bidirectional, and chemokine receptor activa-tion
was shown to inactivate opioid receptor activity in vitro
[13–15]. Of potential functional significance was the finding
that cross-desensitization of CC chemokine receptor 5 (CCR5)
by opioids resulted in decreased susceptibility to R5 but not
X4 strains of human immunodeficiency virus type 1 (HIV-1)
[16].
Recent reports from several laboratories have shown that the
phenomenon of cross-desensitization occurs between a number
of GPCRs, including several of the chemoattractant GPCRs
[14]. It has been suggested recently that the Gi protein-linked
chemoattractant receptors exhibit a hierarchy in producing
cross-desensitization, and this is correlated inversely with their
susceptibility to desensitization [17]. There is clearly a hier-archy
in the cross-desensitization between opioid and chemo-kine
receptors, as -opioid receptor-induced desensitization
does not target the high-affinity formyl peptide receptor (FPR)
or CXC chemokine receptor 4 (CXCR4). In contrast, signaling
from CXCR4 was able to target the - and -opioid receptors,
suggesting that CXCR4 is a relatively potent desensitizer.
Studies reported at this time suggest that heterologous desen-sitization
can involve target receptor phosphorylation or the
alteration of downstream signaling events such as the inhibi-tion
of phospholipase C activity. It is clear that cross-desensi-tization
of GPCRs occurs in many cases as a result of activation
of second messenger protein kinases [protein kinase A (PKA)
or PKC]. These serine/threonine kinases can act directly on
GPCRs and result in receptor desensitization by inhibiting the
coupling of G proteins to the receptor. Target receptor phos-phorylation
is a component of the cross-desensitization of
CXCR1 and CXCR2 by opioid receptors [12], as is the desen-sitization
of the -opioid receptor by CCL5 [13, 15]. Indeed,
target cell phosphorylation is a common observation for cross-desensitization
among several of the chemoattractant receptors
[17–20]. However, simple receptor phosphorylation does not
provide an explanation for cross-desensitization in all cases,
including the desensitization of FPR by C5aR or CXCR2 [17].
Fig. 1. Summary of the process of heterologous desensitization, in which
activation of a GPCR induces a signaling process, which leads to the inacti-vation
of a susceptible, unrelated GPCR (GPCR2), but unsusceptible GPCRs
(GPCR3) remain unaffected.
Adler and Rogers Chemokines and the brain 1205

3. The biochemical basis for the selectivity that exists in the
cross-desensitization process remains undefined at this time.
Although the evidence clearly demonstrated that heterolo-gous
desensitization between opioid and chemokine receptors
occurred in vitro, an unanswered question was whether some of
the chemokines might have the ability to desensitize opioid
receptors in vivo. Such a finding was necessary to determine
whether the in vitro findings are physiologically relevant. We
predicted that the administration of a chemokine should be
able to block or diminish the effect of an opioid without
producing an effect of its own. We found that the analgesic
response to opioids in a rat model, as determined by measuring
the ability of a drug to increase the threshold to a noxious
stimulus (the rat cold water tail-flick test [21]), was inhibited
following chemokine administration. Animals were adminis-tered
a range of doses of CXCL12 or CCL5 directly into the
periaqueductal gray (PAG), the area primarily involved in the
antinociceptive effects of opioids, 30 min prior to morphine or
D-Ala2, NMe-Phe4-Glyol5 (DAMGO), a selective agonist at the
-opioid receptor. These chemokines interfered with the nor-mal
analgesic response to the opioids [13].
To examine temporal aspects of the desensitization, the
system was probed further. The question posed was whether
the desensitization would still occur if the time interval be-tween
administration of the chemokine and the opioid were
increased. It was found that if the CCL5 treatment was given 60
min prior to the opioid, analgesia was only partially blocked,
but if the interval was increased to 2 h, the ability of CCL5 to
desensitize the opioid receptor was lost. It is interesting that if
the time interval was 2 h or greater, and the chemokine was
readministered, the inhibition of the analgesic activity of
DAMGO was restored [13]. A logical explanation is that the
cross-desensitization of the opioid receptor is a reversible
process. A testable hypothesis is that the ligand is metabolized
as it is released from the receptor, and the reinstatement of the
inhibition of opioid receptor function occurs with restoration
with fresh chemokine ligand. It is also possible that new
receptors are expressed on the cell surface, permitting addi-tional
ligand to bind. Formal proof regarding mechanisms has
not been obtained, but we have found that there is no detect-able
internalization of the chemokine or opioid receptor fol-lowing
cross-desensitization in primary leukocytes or in a
number of leukocyte and nonleukocyte cell lines [13, 22].
Finally, it has also been shown that the cross-desensitization
process is associated with target receptor phosphorylation [22].
Furthermore, the heterologous desensitization between CCR5
and the -opioid receptor is also associated with the formation
of heterodimers composed of these two receptors [22].
Although the time course was slightly different with
CXCL12 (the inhibition of opioid receptor function lasts for
60 min longer), the kinetic patterns for reversible inhibition
of opioid receptor function were observed for CXCL12 and
CCL5 [13]. The experiments cited thus far demonstrated that
the -opioid receptor can be desensitized by treatment with
certain chemokines. To determine if the -opioid and the
-opioid receptors could also be cross-desensitized in vivo,
D-Pen2, D-Pen5-enkephalin, a selective -agonist, and dynor-phin
A 1–17, the endogenous opioid, which is a selective
-agonist, were also tested. The - and -opioid receptors were
cross-desensitized by treatment with CCL5 or CXCL12, indi-cating
that desensitization of all three opioid receptors is
achieved with activation of CCL5 and CXCL12 chemokine
receptors [13] (and unpublished results from our laboratories).
These chemokine receptors are expressed on neurons in mul-tiple
areas of the brain, including the PAG [6].
To demonstrate that the chemokine actions are mediated via
the chemokine receptors, the effect of AMD 3100, an antago-nist
at the receptor for CXCL12, was tested. The antagonist
abolished the desensitization, allowing for full analgesic activ-ity
of DAMGO at the -opioid receptor (unpublished observa-tions).
These results confirm that the chemokine-induced de-sensitization
was mediated through the chemokine receptor.
Another chemokine that is expressed in the brain is
CX3CL1. Bajetto et al. [2] reported that this was the only
chemokine found to be expressed in higher concentrations in
the central nervous system (CNS) than in the immune system
and peripheral tissues. Like the other chemokines tested,
CX3CL1 itself had no antinociceptive effect. Nevertheless,
activation of the fractalkine receptor was able to partially block
the antinociceptive action of DAMGO, the -opioid receptor
agonist. Similarly, CX3CL1 also partially blocked the analge-sic
effects of a -selective agonist and a -selective agonist
(unpublished observations). The basis for the inability of CX3C
chemokine receptor 1 (CX3CR1) to inhibit cannabinoid recep-tor
function in the PAG is currently under investigation.
Although CCL5, CXCL12, and CX3CL1 desensitized opioid
receptors, the desensitization did not occur with all chemo-kines.
For example, CCL2 did not induce the cross-desensiti-zation
of the opioid receptors. The reason probably lies in the
fact that the CCL2 receptor, CCR2, is not expressed by neurons
in the PAG matter at a significant level [4], and all injections
were directly into the PAG.
We have suggested [13, 14, 23] that the implication of these
results is that in situations where there is an elevation of
chemokine levels in the brain (including most neuroinflamma-tory
diseases such as multiple sclerosis and HIV encephalitis),
there is a resulting loss of opioid receptor function, leading to
greater sensitivity to painful stimuli. These results provide
evidence of significant functional modulation of neural pro-cesses
by chemokines and their receptors and support the
notion that there is a clear role for chemokines in neural
communication. Indeed, evidence based on the expression
and functional activity of the chemokines and/or their re-ceptors
provides convincing support for our hypothesis that
the chemokine system plays a major role in brain function
(Table 2).
HYPOTHESIS
The systems of neurotransmitters and neuropeptides in the
brain are accepted as playing the major role in the functioning
of the brain in maintaining homeostasis and reacting to per-turbations
of that homeostasis. We propose that the endoge-nous
chemokine system in the brain, consisting of ligands and
receptors, is a third major system of the brain. It is the third leg
in the stool that supports brain function.
1206 Journal of Leukocyte Biology Volume 78, December 2005 http://www.jleukbio.org

4. TABLE 2. The Chemokine System Plays a Major Role in Brain Function
Type of evidence Description of evidence
Expression 1. The chemokines and their receptors are located selectively in areas throughout the brain, including hypothalamus,
nucleus accumbens, limbic system, hippocampus, thalamus, olfactory bulbs, cortex, and cerebellum [4–6].
2. Those chemokines with selective distribution in brain neurons and glia include CCL2, CCL3, CCL5, CXCL10,
CXCL12, and CX3CL1 [1, 24].
3. The receptors for several of the chemokines are expressed specifically by brain neurons [3, 6].
4. CCR5 and CXCR4 in neurons are localized in the perikaryon in a vesicular or granular pattern and extend into
the dendritic processes and axons [25].
5. CXCR4 coexists with neurotransmitters in neurons in the caudate putamen and substantia nigra [6]. Coexistence
with neurotransmitters may indicate an interaction of the two systems, especially if there is co-release.
6. Individual neurons appear to co-express multiple functional chemokine receptors and chemokines [7].
There is certainly no longer any question that chemokines
have important actions in the brain and that they are neuro-active
compounds that have direct and indirect actions on
neurons. Bajetto et al. [28] suggested that chemokines might
act as neuromodulators, and Tran and Miller [31] asked, “Do
chemokines play some unexpected role in the physiology of the
normal brain?” Given the evidence that has accumulated in the
past 5–7 years, it is reasonable to use the above hypothesis
relating to the chemokine system in the brain to begin to make
testable predictions.
The importance of the chemokine system in the brain and its
role in the functioning of the brain in homeostatic and per-turbed
situations is just beginning to be appreciated. This is
apparent in studies about the role of CXCL12 and CXCR4 in
brain development. CXCL12 and its receptor CXCR4 are re-quired
for normal brain development, based on the abnormal
neuronal organization in the cerebellum of CXCR4- or
CXCL12-deficient mice [32–34]. The absence of this chemo-kine
or the receptor appears to result in a premature migration
of external granule cells into the cerebellum [32, 35], and it has
been suggested that CXCL12 may normally act to prevent
excessive migration of these granular cells by chemoattracting
them away from the inner cerebellum and toward the pia matter
overlying the cerebellum [32, 35–37]. In addition, the absence
of CXCR4 leads to an absence of proliferating cells in the
dentate gyrus, and neurons in this anatomic site appear to
differentiate prematurely before completing migration [33]. It
is likely that a role for CXCL12 persists through adult life by
virtue of the role of this chemokine in promoting neuronal
survival and proliferation.
Figure 2 illustrates the concept being proposed in this
paper. It is known that there are glia-to-glia and glia-to-neuron
methods of communication, and it is known that glia can
produce and release chemokines. In light of the more recent
knowledge that chemokines and their receptors are also
present in neurons, we hypothesize that there is also neuron-to-
glia communication involving the chemokines. It is even
more important that we hypothesize that neuron-to-neuron
communication involves an additional system, the chemokine
system of ligands and receptors. Thus, in addition to neuropep-tides
and neurotransmitters performing the vital function of
transmission between neurons, we propose that chemokines
participate in this function. Given the complexity of neuronal
function under normal conditions and when perturbed, recog-nition
of the chemokine system as potentially playing a vital
role in brain functioning would allow another layer of interact-ing
molecules to explain how the neuronal system achieves
such magnificent control of discrete physical, behavioral, and
chemical action and to envision new approaches to treat per-turbations
in homeostasis and enhance brain activity in non-pathological
states.
Functional activity 1. Chemokines are involved in neuronal development [2].
2. CXCL12 reduces the amplitude of evoked excitatory postsynaptic currents in Purkinje neurons in a dose-dependent
manner [26].
3. Functional chemokine receptors on astrocytes can release glutamate, which affects neuronal excitability [27].
4. CXCR4 appears to be involved in the induction of neuronal apoptosis [28].
5. CXCR4-mediated signal transduction may be involved in neuronal dysfunction during HIV-1-associated dementia
[29].
6. Chemokine receptor activation in neurons induces calcium transients and modulates ion channel activity [27].
7. CXCL12 may be involved in neuronal communication [30] and even cholinergic and dopaminergic
neurotransmission [6].
Fig. 2. Each of the three major communication systems plays a role in the
interactions between neurons. In addition, these systems are a critical part of
the communication between neurons and glia in the CNS.
Adler and Rogers Chemokines and the brain 1207

5. WHAT NEEDS TO BE DONE
This paper has put forth the postulate that chemokines function
as transmitters in neuron-to-neuron, glia-to-neuron, and neu-ron-
to-glia communication. Glia-to-glia communication for
chemokines is well established based on experimental results
from a large number of laboratories. For obvious reasons, we
will not endeavor to review all of the criteria, which have
established that neurochemical systems of the brain, such as
those involving acetylcholine, dopamine, and serotonin, are
transmitters. Most modern physiology, neurochemistry, and
neuropharmacology texts discuss these criteria. Despite the
fact that neuropeptides have been studied for over 30 years, not
all the criteria have as yet been met [11] to allow neuropeptides
to be called neurotransmitters. Nevertheless, neuroscientists
universally accept their important role in neuron-to-neuron
communication. As it is a system that has only recently been
found to be involved in brain function, much remains to be
discovered about the chemokine system. For example, the
mechanism of release from neurons, the storage mechanisms,
and the inactivation mechanisms are not known. Specifically,
experiments to determine if selected chemokines can induce or
alter neuronal responses (e.g., using patch-clamp technology)
would be desirable and would provide needed information
regarding a possible role for the chemokines in neurotransmis-sion.
Experiments should also be conducted to determine the
consequences of administration of transmitter combinations
following in vivo administration, as this will more accurately
reflect the normal physiology. Finally, experiments that take
advantage of the growing list of chemokine and chemokine
receptor-deficient mouse strains will likely illuminate the po-tential
role of those chemokine receptors and their ligands in
the response of the brain to various stimuli. One notable
example of this strategy is the recent work with CX3CR1-
deficient mouse strains. As noted above, CX3CR1 and
CX3CL1 are expressed in the brain, and CX3CR1 is present on
microglia and certain neurons, suggesting a possible mode of
communication between these two cell populations. However,
studies with knockout mice do not currently suggest that this
chemokine receptor pair plays a critical role in microglial cell
development or activation [38, 39].
Little information exists as to specific functional systems in
the brain linked to individual chemokines. However, this last
issue also pertains to neuropeptides. Despite the paucity of
data in terms of some of these matters, current evidence is
consistent with the hypothesis that the chemokine system acts
as a major system in the brain to facilitate or be an actual
chemical system of ligands and receptors, which transmits
information in a manner analogous to neurotransmitters and
neuropeptides.
POTENTIAL THERAPEUTIC SIGNIFICANCE
In conclusion, several novel, potential therapeutic applications
can be envisioned by coupling the capacity for heterologous
desensitization of the opioid and chemokine systems with
knowledge about the neuronal function of the chemokine sys-tem.
First, it may be possible to improve the treatment of pain
associated with neuroinflammatory states by blocking heterol-ogous
desensitization of opioid receptors. Again, the chemo-kine-
mediated cross-desensitization of the opioid receptors
appears to account for diminished efficacy of opioids in inflam-matory
pain. Second, the reverse strategy may be used in which
certain unwanted side-effects of opioids may be inhibited by
using chemokine desensitization of selected opioid pathways
after determining neuronal localization of chemokine recep-tors.
Third, we have already reported that the opioid-induced
cross-desensitization of CCR5, a major coreceptor for entry of
HIV in the CNS or periphery, results in reduced HIV suscep-tibility
[16]. Moreover, the cross-desensitization of CCR5 and
CXCR4 by other GPCRs, including the FPRs, has been shown
to result in the loss of HIV coreceptor function [14, 18–20].
Fourth, one may use the cross-desensitizing effects of chemo-kines
to modify the potency of drugs of abuse. A similar
strategy may be used to provide improved control of the activity
of certain behavior-modifying, therapeutic agents used to treat
certain mental disorders. Finally, it is conceivable that new
approaches to prevention and treatment of neurodegenerative
diseases may be achieved through blocking or enhancing the
functional activity of the chemokines by selectively inducing or
inhibiting, repectively, the cross-desensitization of these re-ceptors.
Each of these strategies will require a much greater
understanding of the biochemical basis for the process of
heterologous desensitization. Furthermore, any workable, ther-apeutic
strategy will require intervention in a highly selective
manner to avoid the undesirable consequences of widespread
cross-desensitization of a large number of GPCRs. Perhaps the
necessary degree of selective targeting of the GPCR of interest
can be developed once a greater understanding of the biochem-istry
is achieved. The molecular basis for the heterologous
desensitization process is a major focus of our current work.
ACKNOWLEDGMENTS
The research reported here from the laboratories of Temple
University Center for Substance Abuse Research (CSAR) was
supported by numerous grants, especially DA06650,
DA07237, DA14230, and DA-P30-13429 from the National
Institute on Drug Abuse. The authors acknowledge the contri-bution
of numerous members of the CSAR in conducting
experiments and helping to develop the ideas that led to the
hypothesis about the role of the chemokine system in brain
function. Foremost among those are Dr. Toby K. Eisenstein and
Ms. Ellen B. Geller. In addition, the scientific input of the
laboratories of Drs. Lee-Yuan Liu-Chen, Ronald J. Tallarida,
Alan Cowan, Ellen M. Unterwald, Xiaohong Chen, and Khalid
Benamar and the technical assistance of Margaret Deitz are
gratefully acknowledged.
REFERENCES
1. Ambrosini, E., Aloisi, F. (2004) Chemokines and glial cells: a complex
network in the central nervous system. Neurochem. Res. 29, 1017–1038.
1208 Journal of Leukocyte Biology Volume 78, December 2005 http://www.jleukbio.org

6. 2. Bajetto, A., Bonavia, R., Barbero, S., Florio, T., Schettini, G. (2001)
Chemokines and their receptors in the central nervous system. Front.
Neuroendocrinol. 22, 147–184.
3. van der Meer, P., Ulrich, A. M., Gonza´lez-Scarano, F., Lavi, E. (2000)
Immunohistochemical analysis of CCR2, CCR3, CCR5, and CXCR4 in the
human brain: potential mechanisms for HIV dementia. Exp. Mol. Pathol.
69, 192–201.
4. Banisadr, G., Que´raud-Lesaux, F., Boutterin, M. C., Pe´laprat, D., Zalc, B.,
Roste`ne, W., Haour, F., Parsadaniantz, S. M. (2002) Distribution, cellular
localization and functional role of CCR2 chemokine receptors in adult rat
brain. J. Neurochem. 81, 257–269.
5. Horuk, R., Martin, A. W., Wang, Z., Schweitzer, L., Gerassimides, A.,
Guo, H., Lu, Z., Hesselgesser, J., Perez, H. D., Kim, J., Parker, J., Hadley,
T. J., Peiper, S. C. (1997) Expression of chemokine receptors by subsets
of neurons in the central nervous system. J. Immunol. 158, 2882–2890.
6. Banisadr, G., Fontanges, P., Haour, F., Kitabgi, P., Roste`ne, W., Parsada-niantz,
S. M. (2002) Neuroanatomical distribution of CXCR4 in adult rat
brain and its localization in cholinergic and dopaminergic neurons. Eur.
J. Neurosci. 16, 1661–1671.
7. Coughlan, C. M., McManus, C. M., Sharron, M., Gao, Z-Y., Murphy, D.,
Jaffer, S., Choe, W., Chen, W., Hesselgesser, J., Gaylord, H., Kalyuzhny,
A., Lee, V. M. Y., Wolf, B., Doms, R. W., Kilson, D. L. (2000) Expression
of multiple functional chemokine receptors and monocyte chemoattractant
protein-1 in human neurons. Neuroscience 97, 591–600.
8. Ji, J. F., He, B. P., Dheen, S. T., Tay, S. S. W. (2004) Expression of
chemokine receptors CXCR4, CCR2, CCR5 and CX3CR1 in neural pro-genitor
cells isolated from the subventricular zone of the adult rat brain.
Neurosci. Lett. 355, 236–240.
9. Hickey, W. F., Hsu, B. L., Kimura, H. (1991) T-lymphocyte entry into the
central nervous system. J. Neurosci. Res. 28, 254–260.
10. Carrithers, M. D., Visintin, I., Viret, C., Janeway, C. A. (2002) Role of
genetic background in P selectin-dependent immune surveillance of the
central nervous system. J. Neuroimmunol. 129, 51–57.
11. Cooper, J. R., Bloom, F. E., Roth, R. H. (2003) The Biochemical Basis of
Neuropharmacology, New York, NY, Oxford University Press.
12. Grimm, M. C., Ben-Baruch, A., Taub, D. D., Howard, O. M., Resau, J. H.,
Wang, J. M., Ali, H., Richardson, R., Snyderman, R., Oppenheim, J. J.
(1998) Opiates transdeactivate chemokine receptors: and opiate
receptor-mediated heterologous desensitization. J. Exp. Med. 188, 317–
325.
13. Szabo, I., Chen, X. H., Xin, L., Adler, M. W., Howard, O. M. Z.,
Oppenheim, J. J., Rogers, T. J. (2002) Heterologous desensitization of
opioid receptors by chemokines inhibits chemotaxis and enhances the
perception of pain. Proc. Natl. Acad. Sci. USA 99, 10276–10281.
14. Steele, A. D., Szabo, I., Bednar, F., Rodgers, R. J. (2002) Interactions
between opioid and chemokine receptors: heterologous desensitization.
Cytokine Growth Factor Rev. 13, 209–222.
15. Rogers, T. J., Steele, A. D., Howard, O. M. Z., Oppenheim, J. J. (2000)
Bidirectional heterologous desensitization of opioid and chemokine recep-tors.
Ann .N. Y. Acad. Sci. 917, 19–28.
16. Szabo, I., Wetzel, M. A., Zhang, N., Steele, A. D., Kaminsky, D. E., Chen,
C., Liu-Chen, L-Y., Bednar, F., Henderson, E. E., Howard, O. M. Z.,
Oppenheim, J. J., Rogers, T. J. (2003) Selective inactivation of CCR5 and
decreased infectivity of R5 HIV-1 strains mediated by opioid-induced
heterologous desensitization. J. Leukoc. Biol. 74, 1074–1082.
17. Ali, H., Richardson, R. M., Haribabu, B., Snyderman, R. (1999) Chemoat-tractant
receptor cross-desensitization. J. Biol. Chem. 274, 6027–6030.
18. Shen, W., Li, B., Wetzel, M. A., Rogers, T. J., Henderson, E. E., Su, S. B.,
Gong, W., Le, Y., Sargeant, R., Dimitrov, D. S., Oppenheim, J. J., Wang,
J. M. (2000) Down-regulation of the chemokine receptor CCR5 by acti-vation
of chemotactic formyl peptide receptor in human monocytes. Blood
96, 2887–2894.
19. Le, Y., Wetzel, M. A., Shen, W., Gong, W., Rogers, T. J., Henderson,
E. E., Wang, J. M. (2001) Desensitization of chemokine receptor CCR5 in
dendritic cells at the early stage of differentiation by activation of formyl
peptide receptors. Clin. Immunol. 99, 365–372.
20. Li, B. Q., Wetzel, M. A., Mikovits, J. A., Henderson, E. E., Rogers, T. J.,
Gong, W., Le, Y., Ruscetti, F. W., Wang, J. M. (2001) The synthetic
peptide WKYMVm attenuates the function of the chemokine receptors
CCR5 and CXCR4 through activation of formyl peptide receptor-like 1.
Blood 97, 2941–2947.
21. Pizziketti, R. J., Pressman, N. S., Geller, E. B., Cowan, A., Adler, M. W.
(1985) Rat cold water tail-flick: a novel analgesic test that distinguishes
opioid agonists from mixed agonist-antagonists. Eur. J. Pharmacol. 119,
23–29.
22. Chen, C., Li, J., Bot, G., Szabo, I., Rogers, T. J., Liu-Chen, L-Y. (2004)
Heterodimerization and cross-desensitization between the -opioid recep-tor
and the chemokine CCR5 receptor. Eur. J. Pharmacol. 483, 175–186.
23. Rogers, T. J., Peterson, P. K. (2003) Opioid G protein-coupled receptors:
signals at the crossroads of inflammation. Trends Immunol. 24, 116–121.
24. Mizuno, T., Kawanokuchi, J., Numata, K., Suzumura, A. (2003) Production
and neuroprotective function of fractalkine in the central nervous system.
Brain Res. 979, 65–70.
25. Westmoreland, S. V., Alvarez, X., Debakker, C., Aye, P., Wilson, M. L.,
Williams, K. C., Lackner, A. A. (2002) Developmental expression patterns
of CCR5 and CXCR4 in the rhesus macaque brain. J. Neuroimmunol.
122, 146–158.
26. Ragozzino, D., Renzi, M., Giovannelli, A., Eusebi, F. (2002) Stimulation
of chemokine CXC receptor 4 induces synaptic depression of evoked
parallel fibers inputs onto Purkinje neurons in mouse cerebellum. J. Neu-roimmunol.
127, 30–36.
27. Cho, C., Miller, R. J. (2002) Chemokine receptors and neural function.
J. Neurovirol. 8, 573–584.
28. Bajetto, A., Bonavia, R., Barbero, S., Schettini, G. (2002) Characterization
of chemokines and their receptors in the central nervous system: physio-pathological
implications. J. Neurochem. 82, 1311–1329.
29. Zheng, J., Thylin, M. R., Ghorpade, A., Xiong, H., Persidsky, Y., Cotter,
R., Niemann, D., Che, M. H., Zeng, Y-C., Gelbard, H. A., Shepard, R. B.,
Swartz, J. M., Gendelman, H. E. (1999) Intracellular CXCR4 signaling,
neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated
dementia. J. Neuroimmunol. 98, 185–200.
30. Stumm, R. K., Rummell, J., Junker, V., Culmsee, C., Pfeiffer, M., Krieg-istein,
J., Ho¨llt, V., Schulz, S. (2002) A dual role for the SDF-1/CXCR4
chemokine receptor system in adult brain: isoform-selective regulation of
SDF-1 expression modulates CXCR4-dependent neuronal plasticity and
cerebral leukocyte recruitment after focal ischemia. J. Neurosci. 22,
5865–5878.
31. Tran, P. B., Miller, R. J. (2003) Chemokine receptors in the brain: a
developing story. J. Comp. Neurol. 457, 1–6.
32. Ma, Q., Jones, D., Borghesani, P. R., Segal, R. A., Nagasawa, T., Kishi-moto,
T., Bronson, R. T., Springer, T. A. (1998) Impaired B-lymphopoie-sis,
myelopoiesis, and derailed cerebellar neuron migration in CXCR4-
and SDF-1-deficient mice. Proc. Natl. Acad. Sci. USA 95, 9448–9453.
33. Lu, M., Grove, E. A., Miller, R. J. (2002) Abnormal development of the
hippocampal dentate gyrus in mice lacking the CXCR4 chemokine recep-tor.
Proc. Natl. Acad. Sci. USA 99, 7090–7095.
34. Bagri, A., Gurney, T., He, X., Zou, Y. R., Littman, D. R., Tessier-Lavigne,
M., Pleasure, S. J. (2002) The chemokine SDF1 regulates migration of
dentate granule cells. Development 129, 4249–4260.
35. Zou, Y. R., Kottmann, A. H., Kuroda, M., Taniuchi, I., Littman, D. R.
(1998) Function of the chemokine receptor CXCR4 in haematopoiesis and
in cerebellar development. Nature 393, 595–599.
36. McGrath, K. E., Koniski, A. D., Maltby, K. M., McGann, J. K., Palis, J.
(1999) Embryonic expression and function of the chemokine SDF-1 and
its receptor, CXCR4. Dev. Biol. 213, 442–456.
37. Zhu, Y., Yu, T., Zhang, X. C., Nagasawa, T., Wu, J. Y., Rao, Y. (2002)
Role of the chemokine SDF-1 as the meningeal attractant for embryonic
cerebellar neurons. Nat. Neurosci. 5, 719–720.
38. Jung, S., Aliberti, J., Graemmel, P., Sunshine, M. J., Kreutzberg, G. W.,
Sher, A., Littman, D. R. (2000) Analysis of fractalkine receptor CX(3)CR1
function by targeted deletion and green fluorescent protein reporter gene
insertion. Mol. Cell. Biol. 20, 4106–4114.
39. Cook, D. N., Chen, S. C., Sullivan, L. M., Manfra, D. J., Wiekowski, M. T.,
Prosser, D. M., Vassileva, G., Lira, S. A. (2001) Generation and analysis
of mice lacking the chemokine fractalkine. Mol. Cell. Biol. 21, 3159–
3165.
Adler and Rogers Chemokines and the brain 1209