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6111.Carr J.J. Blaloek J.E. - Opioid µ δ and κ Receptors for Endorphins (2000).pdf

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Opioid , , and
Receptors for
Endorphins
Daniel J. J. Carr1 and J. Edwin Blalock2,*
1
Department of Microbiology and Immunology, LSU Medical Center, New Orleans,
LA 70112-1393, USA
2
Department of Physiology and Biophysics, University of Alabama at Birmingham,
Birmingham, AL 35294-0005, USA
* corresponding author tel: 205-934-6439, fax: 205-934-1446, e-mail: blalock@uab.edu
DOI: 10.1006/rwcy.2000.23005.
SUMMARY
The three major types of opioid receptors (, , and )
are members of the DRY (Asp-Arg-Tyr)-containing
subfamily of seven transmembrane spanning receptors. Opioid receptors on cells of the immune system
are virtually identical to those on neuronal cells. The
activation of opioid receptors in the CNS leads to
analgesia while activation of opioid receptors on
immune cells can enhance or suppress immune function depending on the target cell and immune parameter measured.
BACKGROUND
Discovery
The molecular characterization of opioid receptors
has been investigated for nearly 25 years. However,
the activities of these receptors, as manifested in the
effects of opioid compounds (e.g. opium, of which the
main active ingredient is morphine), have been known
for at least 6000 years, since the time of the Sumerians
(4000 BC). The discovery of endogenous opioid peptides, including the enkephalins (met- and leuenkephalin) (Hughes et al., 1975), the endorphins
(, , and ) (Bradbury et al., 1976; Cox et al., 1976),
dynorphin (Goldstein et al., 1979), and endomorphin
(Zadina et al., 1997), suggested the existence of
multiple types of receptors (termed opioid receptors)
for these natural ligands. Evidence for multiple types
of opioid receptors was obtained using congeners of
morphine in spinal studies in dogs (Gilbert and Martin,
1976; Martin et al., 1976).
Originally identified in the early 1970s (Pert and
Snyder, 1973; Simon et al., 1973; Terenius, 1973),
today, three main types of opioid receptors have been
defined and cloned: , , and opioid receptors with
pharmacologically distinct subtypes for (1 and 2),
(1, 2, and 3), and (1 and 2) (Pasternak,
1993). Two other receptors including " (specific for endorphin) and receptors were originally described
as opioid receptors but have since been redefined as
nonopioid (Simon, 1991). All of these receptors have
been identified and characterized on cells of the
immune system (Garza and Carr, 1997).
Another opioid-like receptor, referred to as the
nociceptive receptor (orphan opioid receptor), originally described in human brainstem (Mollereau et al.,
1994) was also found in mouse spleen T and B lymphocytes, where it was first coupled to a physiological
role (Halford et al., 1995). This review focuses on the
immune cell-derived opioid receptors, comparing their
physicochemical properties with those found in the
2212 Daniel J. J. Carr and J. Edwin Blalock
nervous system as well as defining their role in the
immune system.
Structure
The three major types of opioid receptors are members of the (DRY)-containing subfamily of seven
transmembrane spanning receptors. There is 60%
amino acid identity between each type of opioid receptor with the membrane-spanning regions (transmembrane I±VII) and the intracellular loops connecting
these segments being highly conserved between receptor types. Studies indicate that ligands (agonists and
antagonists) to these receptors bind to different
regions of the extracellular domain and such interaction can be greatly influenced by the transmembrane segments (predominantly TM II, III, and VI)
(Kong et al., 1993, 1994; Surratt et al., 1994). Also,
changes in one amino acid in the TM IV spanning
region has been shown to alter opioid antagonist to
agonist activity (Claude et al., 1996). Since the amino
acid sequences of the neuronal- and some immunederived receptors are nearly identical, it is predicted
that a similar relationship between agonist/antagonist-binding domains and the influence of the transmembrane spanning regions will be found in the
immune-derived opioid receptors. However, immunederived opioid receptor-binding domains according
to some investigators may be distinct since binding
or biochemical characteristics of these sites are not
characteristic of neuronal opioid sites (e.g. Stefano
et al., 1992; Makman et al., 1995).
Main activities and
pathophysiological roles
The primary function associated with neuronal opioid
receptors is the control of the sensation of pain either
through receptors located spinally (1, 1, and 2) or
supraspinally (2, 2, 3, and 1) (Pasternak, 1993).
Within the immune system, opioid receptors found on
immune cells may augment or suppress immune function depending on the cell type and stimulation (Carr,
1991). However, alkaloid opioid ligands (e.g. morphine and fentanyl) are potent immunosuppressive
compounds affecting the immune system primarily by
indirect pathways ligating to receptors found within
the CNS and activating secondary systems (including
the adrenergic pathway and the hypothalamuspituitary-adrenal axis) (Carr et al., 1996). Other functions of immune-derived opioid receptors may pertain
to the response to infectious pathogens. As an
example, opioid receptors bound to -selective
opioid ligands have been found to reduce significantly
monocytotropic HIV-1 SF162 strain replication in
microglia-enriched cultures (Chao et al., 1996).
GENE
Accession numbers
The (L06322, L11065), (L11064), and (L22455,
L20684) opioid receptors have been cloned from neuronal tissue (Evans et al., 1992; Kieffer et al., 1992;
Li et al., 1993; Thompson et al., 1993; Wang et al.,
1993; Yasuda et al., 1993).
PROTEIN
Accession numbers
Protein Information Resource:
Human opioid receptor: 2135858
Human opioid receptor: 631277
Human opioid receptor: 2134989
Sequence
The neuronal opioid receptors are composed of
between 370 and 389 amino acids encoded by mRNAs
ranging in size from 1.9 to > 10.0 kb (Carr et al.,
1996). Both (Figure 1a; Sedqi et al., 1996) and (Figure 1b; Belkowski et al., 1995) receptor full-length
cDNAs (predicted to be 372±400 amino acids in
length) have been identified in thymocytes or a
thymoma cell line. However, only a partial sequence
(441 bp) of a opioid receptor has been identified by
RT-PCR in peripheral blood mononuclear cells
(Chuang et al., 1995) and rat peritoneal macrophages
(Figure 1c; 721 bp) (Sedqi et al., 1995). All immune
cell-derived receptor sequences identified thus far are
nearly identical ( 99% homology) with the receptors
in the nervous system.
Description of protein
By a variety of techniques, the neuronal opioid receptors were observed to range in size from 40 to 65 kDa
(Simonds, 1988; Loh and Smith, 1990; Wollemann,
1990). The data concerning the biochemical properties of these receptors may be limited by the uncertain
specificities of some of the antireceptor antisera.
Opioid , , and Receptors for Endorphins 2213
Figure 1 (a) Deduced amino acid sequence
of the opioid receptor cloned from
activated murine thymocytes as reported
by Sedqi et al. (1996). Bold letters indicate
changes from the published rodent brain opioid receptor. (b) Deduced amino acid
sequence of the opioid receptor cloned
from R1.1 thymoma cell line as reported by
Alicea et al. (1998). Bold letters indicate
changes from the published rodent brain opioid receptor. (c) Deduced amino acid sequence of the opioid receptor cloned from
adherent peritoneal macrophages as reported
by Sedqi et al. (1995). Bold letters indicate
changes from the published rodent brain opioid receptor.
(a)
MELVPSARAELQSSPLVNLSDAFPSAFPSA
GANASGSPGARSASSLALAIAITV LYSAVC
AVGLLGNVLVMFGIVRYTKLKTATNIYIFN
LALADALATSTI PFQSAKYLMETWPFGELL
CKAVLSIDYYNMFTSIFTLTMMSVDRYIAV
CHPVKALDFRTPAKAKLIQ ICIWVLASGVG
VPIMVMAVTQPRDGAVVCMLQFPSPSWYWD
TVTKICVFLFAFVVPILIITVCYGLMLLRL
RSVRLLSGSKEKDRSLRRITRMVLVVVGAF
VVCWAPIHIFVIVWTLVDINRRDPLVVAAL
HLCIALGYANSSLNPVLYAFLDENFKRCFR
QLCRTPCGRQEPGSLRRPRQATTRERVTAC
TPSDGPGGGAAA
30
60
90
120
150
180
210
240
270
300
330
360
372
(b)
MESPIQIFRGNPGPTCSPSACLLPDSSSWF
PDWAESNSDGSVGSENQQLESAHISPAIPV
IITAVNSVVFVVGLVGDSLVMFVIIRIYTK
MKTATDIYIFDLALANALVTTTMPFQSAVY
LMDSWPFGNVLCKIVISINYYDMFTSIFTL
TMMSVNRYIAVCHPVKALNFRTPLKAKIID
ICIWLL ASSVGISAIVLGGT KVRENVNVIE
CSLQFPNNEYSWWNLFMKICVFV FAFVIPV
LIIIVCYTLMILRLKSVRVLSGSREKNRDL
RRITKLVLVVVAVFIICWTPIHIFILVEAL
GSTSHSTAALSSYYFCIALGYTDSSLDPVL
YAFLNEDFKRCFRNFCFPIKMRMERQSTDR
DTVQNPASMRNVGGMDKPV
30
60
90
120
150
180
210
240
260
290
320
350
369
labeled proteins migrating at 70, 46, and 31 kDa from
brain tissue, while a major protein species migrating
at 31 kDa was labeled from spleen tissue. The 31 kDa
species was thought to be a degradative form of the
mature protein. Subsequent analysis of immune cellderived , , and opioid receptors determined the
size to be nearly identical to that of the neuronal
receptors (Carr, 1991).
Relevant homologies and species
differences
Opioid receptors from immune cells are virtually
identical ( 99% homology) to those on neuronal
cells. The various opioid receptor types (, , ) show
about 60% homology.
Affinity for ligand(s)
The identification of the types of opioid receptors has
been greatly facilitated by the design and synthesis of
opioid ligands selective for the types of receptors to
which they bind (Table 1). Similar to cell-associated
neuronal opioid receptors, the cloned neuronal opioid
receptors expressed in PC-12 cells showed highaffinity binding to ligands ranging from 0.2 to 3.0 nM
(Raynor et al., 1994). Opioid receptors found on cells
of the immune system display a modestly reduced
affinity for their ligands ranging from 20 to 900 nM,
depending on the ligand and receptor (Garza and
Carr, 1997). For example, receptors display affinities ranging from 4.1 to 65.0 nM (Garza and Carr,
1997), whereas a unique alkaloid-specific 3 opioid
receptor found on granulocytes has a Kd of 44 nM
(Makman et al., 1995). One investigation reported the
IC50 for an immunoaffinity-purified opioid receptor
isolated from mouse spleen preparations to be
approximately 700 nM, suggesting a loss in affinity
upon purification (Carr et al., 1990).
(c)
MGTWPFGTILCKIV ISIDYYNMFTSIFTLC
TMSVDRYIAVCHPVKA LDFRTPRNAKIVNV
CNWILSSAIGLPVMFMATTKYRQGSIDCTL
TFSHPTWYWQNLLKICVFIFAFIMPILIIT
VCYALMILRLKSVRMLSGSKEKNRDLRRITR
MVLVVVAVFIVCWTPIHIYVIIKALITIPE
TTFQTVSWHFCIALGYTDSCLDPVLYAFLN
30
60
90
120
150
180
210
Using a site-directed acylating agent derived from
fentanyl (known as superfit) that is highly selective for
opioid receptors, a comparison of the mouse brain
cell- and spleen cell-derived opioid receptor. Superfit
Cell types and tissues expressing
the receptor
Within the immune system, there is some disagreement as to the population of cells that express opioid
receptors. To this end, Table 2 and Table 3 summarize
the evidence for the presence of opioid receptors on
primary cells of the immune system (Table 2) and
cell lines derived from cells of the immune system
(Table 3) based on pharmacological (radioreceptor
2214 Daniel J. J. Carr and J. Edwin Blalock
Table 1 Commercially available selective opioid agonists/antagonists
Opioid receptor ligands
Opioid receptor ligands
Opioid receptor ligands
DADLE (agonist)
Bremazocine (agonist)
DAMGO (agonist)
DPDPE (agonist)
U-50488 (agonist)
Endomorphin 1 (agonist)
SNC 80 (agonist)
U-69593 (agonist)
Endomorphin 2 (agonist)
DSLET (agonist)
ICI-199,441 (agonist)
Fentanyl citrate (agonist)
SNC121 (agonist)
Nor-binaltorphimine (antagonist)
-Funaltrexamine (antagonist)
Superfit (affinity label)
DIPPA (antagonist)
Naloxonazine (antagonist)
Naltrindole (antagonist)
Cyprodime HBr (antagonist)
ICI-174,864 (antagonist)
BNTX (antagonist)
Naltriben (antagonist)
Table 2 Evidence for the presence of opioid receptors on primary cells of the immune systema
Cell type
Receptor
Receptor
Receptor
Mouse T lymphocyte
B, M
±
B
Mouse B lymphocyte
B
±
B
Mouse thymocyte
±
±
P, M
Mouse splenocyte
B, M
B
B
Human PBLs
M
M
±
Human T lymphocyte
P, B
M
±
Human B lymphocyte
B
±
±
Human granulocyte
±
±
P, M
Human monocyte
±
M
M
Monkey PBLs
M
M
M
Human microglia
±
M
±
Rat macrophage
±
±
M
a
Evidence for the existence of the receptors is defined using pharmacological (P), biochemical (B), or molecular
biology (M) approaches (Alicea et al., 1998; Chao et al., 1996; Gaveriaux et al., 1995; Miller, 1996;
Roy et al., 1992; Wick et al., 1996) or as reviewed by Carr (1991), Carr et al. (1996).
±, Suggests either a lack of detection or that the analysis has not yet been determined.
assays), biochemical (affinity labeling), or molecular
biology techniques (cloning or RT-PCR studies).
Regulation of receptor expression
The expression of and opioid receptors on
immune cells is reportedly induced by the activation
of cells by IL-1 in the case of the thymocyte receptor
(Roy et al., 1992) or mitogen (concanavalin A) in the
case of the mouse T lymphocyte opioid receptor
(Miller, 1996). Furthermore, the activation of leukocytes also leads to the production of endogenous
opioid peptides (Blalock, 1989). Since the leukocytederived opioid peptides have also been shown to be
functionally active (Blalock, 1989), there is reason to
believe that autocrine regulation of receptor expression may occur as well.
Opioid , , and Receptors for Endorphins 2215
Table 3
systema
Evidence for the presence of opioid receptors on cell lines derived from cells of the immune
Cell type
Receptor
Receptor
Receptor
M
M
P
±
±
±
M
±
±
B
P, B
±
P, M
±
M
M
B, M
M
±
M
M
±
±
M
M
M
±
Mouse T cell lines
EL-4
11.10
Mouse B cell line
CH27
Mouse macrophage cell line
P388d1
Mouse R1.1 thymoma
Human T cell lines
CEMx174
HSB2
MOLT-4
Human B cell line
EBV-transformed
Human monocyte cell line
U937
±
a
Evidence for the existence of the receptors is defined using pharmacological (P), biochemical (B), or molecular
biology (M) approaches (Gaveriaux et al., 1995; Chao et al., 1996; Wick et al., 1996; Alicea et al., 1998) or
as reviewed by Carr (1991), Carr et al. (1996).
±, Suggests either a lack of detection or that the analysis has not yet been determined.
SIGNAL TRANSDUCTION
Cytoplasmic signaling cascades
Neuronal opioid receptors modify a variety of
signaling cascades including cAMP through the
activation of Gi, increases in GTPase activity, phosphatidylinositol turnover, mobilization of Ca2+, and
K+ channel activity (Childers, 1991; Chen and Yu,
1994). In a similar fashion, immune cell-derived
opioid receptors are coupled to a Gi protein and
influence K+ channel conductance and calcium
mobilization (Carr, 1991). In addition, the endogenous opioid peptide -endorphin has been shown to
modify CD3 phosphorylation following phorbol
ester stimulation, either increasing or decreasing phosphorylation of the CD3 chain depending on the
concentration of the peptide (Kavelaars et al., 1990).
These results suggest that the endorphins may act as
a governor on T cell activation depending on the
local concentration of endogenous opioid peptide.
Specifically, endorphins at mid-picomolar levels may
augment T cell activation through the increase in
phosphorylation of the CD3 complex intracellular
tyrosine-activation motifs (ITAMs) and presumably
the activation of the inositol trisphosphate (IP3) cascade via ZAP-70, whereas at femtomolar levels the
endorphins would suppress T cell activation by
reducing phosphorylation.
DOWNSTREAM GENE
ACTIVATION
Transcription factors activated
The success in transfecting Jurkat T cells (which do
not express opioid receptors, Gaveriaux et al., 1995)
with a functional opioid receptor (Sharp et al., 1996)
allowed for the identification of potential transcriptional regulatory elements involved in opioid modulation of immune function. Previous studies reported
the augmentation of IL-2 production by activated
T cells stimulated with endogenous opioid peptides
2216 Daniel J. J. Carr and J. Edwin Blalock
(Carr, 1991). In an elegant study, reporter gene constructs were used to map deltorphin ( selective
agonist)-elicited augmentation of IL-2 production by
opioid receptor-transfected Jurkat T cells to the
AP-1- and NF-AT/AP-1-binding site (Hedin et al.,
1997). This effect was apparently independent of
calcineurin and unrelated to the elevation in [Ca2+
i ]
but required pertussis toxin-sensitive G protein. Since
the NF-AT/AP-1 complex is involved in the induction
of a number of cytokine genes (Rao, 1994) and endogenous opioid peptides modify the production of a
number of cytokines (Peterson et al., 1998), it is quite
possible that the NF-AT/AP-1 complex is involved.
In addition, since leukocyte activation is primarily
mediated by cytokines, it is highly probable that
opioid receptor promoters possess binding domains
for cytokine responsive elements. As an example,
the opioid receptor promoter possesses a NF-IL6
domain (Min et al., 1994).
Genes induced
IL-2.
BIOLOGICAL CONSEQUENCES
OF ACTIVATING OR INHIBITING
RECEPTOR AND
PATHOPHYSIOLOGY
Unique biological effects of
activating the receptors
The response to opioid receptor activation depends
on the location of the receptor, the type of receptor,
and the level of activation of the cell population.
Endogenous opioid peptides can either enhance or
suppress immune function depending in part on the
state of target cell activation and the immune parameter (antibody production, natural killer activity,
cytokine synthesis) measured. Likewise, peripheral
blood mononuclear cells from individuals can respond
differently (sometimes completely opposite of one
another) to opioid ligands evident in both human and
mouse populations. However, the administration of
opioid alkaloids (i.e. morphine, heroin, or fentanyl)
tends to elicit a significant suppression of immune
function primarily by opioid receptors found in the
mesencephalon (Shavit et al., 1986; Weber and Pert,
1989).
The activation of the `central' opioid receptors
elicits the activation of neuroendocrine pathways.
The hypothalamic-pituitary-adrenal axis results in
the production of adrenal steroids such as glucocorticoids which suppress immune responses in part
by preventing translocation of NFB to the nucleus
(Baldwin, 1996). Alternatively, morphine may activate the sympathetic/parasympathetic arm of the
autonomic nervous system known to innervate
lymph nodes and spleen (Felten et al., 1987) and
modify immune function through the release of
monoamines (e.g. catecholamines) (Carr and Serou,
1995).
Other studies suggest that endogenous opioid peptides may supplement antimicrobial drugs or local
immune reactivity against viral infections. Studies
have suggested that met-enkephalin suppresses
influenza virus infection in mice through the effects
on natural killer cells and cytotoxic T lymphocytes
(Burger et al., 1995). Another study has found that
met-enkephalin synergizes with azidothymidine in
blocking feline leukemia virus replication (Specter
et al., 1994). It has also been reported that endogenous opioids induce the synthesis of novel fentanyl
derivatives that possess analgesic activity in the
absence of opioid immunosuppression (Carr and
Serou, 1995).
Phenotypes of receptor knockouts
and receptor overexpression mice
Mu opioid receptor (MOR) knockout mice have been
developed and tested for immune deviation in the
presence and absence of the clinically relevant, prototypic ligand morphine. MOR knockout mice exhibit
normal immunological endpoints including natural
killer activity, antibody production, and mitogeninduced lymphocyte proliferation (Gaveriaux-Ruff
et al., 1998). However, bone marrow cells from MOR
knockout mice exhibit an altered pattern of early
hematopoiesis (Tian et al., 1997). In addition, treatment with morphine had no effect on immune
parameters assayed in MOR knockout mice, but significantly suppressed selectively measured immune
parameters (e.g. natural killer cell activity) and
induced lymphoid organ atrophy in wild-type mice
(Gaveriaux-Ruff et al., 1998). These results suggest
that the absence of the opioid receptor has no
detrimental effect on immunocompetence per se, but
is directly responsible for the immunomodulatory
effects of exogenous morphine. Accordingly, modification of immune responses to antigen or microbial
pathogens by endogenous opioid peptides does not
necessarily involve the activation of opioid receptors on immune cells.
Opioid , , and Receptors for Endorphins 2217
THERAPEUTIC UTILITY
Effects of inhibitors (antibodies)
to receptors
The classical pharmacological definition of the existence of opioid receptors on cells of the immune
system has come from the ability of opioid antagonists (competitive or noncompetitive) to block the
immunomodulatory effects in a stereospecific manner
(Sibinga and Goldstein, 1988) (see Table 1). Antibodies have also been generated against opioid receptors that recognize proteins expressed on cells of the
immune system. One such antibody was found to
possess agonist activity and to recognize a putative class opioid receptor on mouse leukocytes (Carr et al.,
1990). A second antibody was generated against the
predicted N-terminal sequence of a opioid receptor
and was found to act as a noncompetitive selective
antagonist recognizing opioid receptors on U937
cells (Buchner et al., 1997). However, the use of antibodies is more apt to focus on characterizing the
structural properties of the cloned receptor (e.g.
mapping ligand-binding domains) rather than using
such antibodies to antagonize tolerance or chemical
dependence.
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