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Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

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Opioid Receptor Expression and Intracellular Signaling by Cells Involved in Host Defense and Immunity


More than two decades ago, Joseph Wybran reported his original insights on the expression of different opioid receptor types by T-cells. This was based on the differential effects that morphine and methionine enkephalin exerted on human T-cell rosetting in the presence of sheep red blood cells. Since that time, numerous laboratories have shown that opiate alkyloids and opioid peptides have pleiotropic effects on immune function. In general, these compounds act as immunomodulators that modify the immune response to mitogens, antigens and antibodies that crosslink the T-cell receptor. In the past decade, it has become clear that T-cells involved in host defense and immunity express the various mRNAs encoding the same opioid receptors originally identified in neuronal tissues. Recently, indirect fluorescence and immunofluorescence have been utilized to demonstrate the regulated expression of both delta and kappa opioid receptors, predominantly on T-cells. In addition, immune cells express sites that show atypical opiate and opioid binding properties. In this review, we will distill the evidence for both classical and atypical opioid receptors and their effects on signaling within immune cells, focusing on the T-cell and emphasizing the δ opioid receptor.


The direct immunomodulatory effects of opiate alkyloids and opioid peptides have been recognized for more than two decades. Thus, β-endorphin and synthetic opioid peptide agonists selective for the δ opioid receptor (DOR) are known to modulate thymic and splenic T-cell proliferation, cytokine production and calcium mobilization.1-4 Selective DOR agonists, such as [D-Ala2-D-Leu5]-enkephalin (DADLE) and deltorphin, were shown to inhibit the anti-CD3-ϵ induced proliferation of highly purified murine splenic CD4+;and CD8 T-cells.2 In addition, interleukin (IL)-2 production was partially suppressed at higher concentrations (10−8 10−6 M) of DADLE and deltorphin. Although these studies provide pharmacological evidence for the presence of DOR on T-cells, the mechanism(s) whereby these compounds modulate the activation and function of cells involved in host defense and immunity has been obscured by the lack of direct evidence for the expression of opioid receptors by these cells. Recent studies from several laboratories have largely resolved this dilemma. This review will focus on observations that have advanced our understanding of the expression and intracellular effects of opioid receptors on lymphocytes and other cells in the peripheral immune system.

The original observations showing that morphine and methionine enkephalin directly affect immune function were made by Joseph Wybran et al.5 His 1979 report demonstrated that these compounds had opposite, yet direct, effects on the rosetting of human T-cells to sheep red blood cells. Based on our current understanding, these effects on T-cell rosetting indicate that opiates modulate the CD2 receptor expressed by T-cells. Based on these disparate effects of morphine and methionine enkephalin, Wybran inferred that human T-cells express different subtypes of opioid receptors that show preferential interactions with and confer differential, and sometimes opposite, cellular responses to these agonists.

Identification of Classical and Atypical Opioid Receptors on Immune Cells by Radioligand Binding

A number of laboratories have reported radioligand binding studies of opiates to immune cells. In many of these, the data sets were incomplete or atypical binding sites were found. Using [3H]naloxone, experiments with freshly obtained human peripheral blood lymphocytes suggested the existence of a morphine-sensitive site, since approximately 40% of the [3H]naloxone was displaced by morphine concentrations in the nM range.6 Amongst the atypical sites, Roy and colleagues reported morphine binding on resting thymocytes, with a relatively low affinity for morphine (approximate Kd = 100 nM).7,8 Similar sites on human peripheral blood macrophages were reported by Makman et al who described a low affinity, naloxone-insensitive binding for morphine, designated μ3.9 Lastly, high affinity, naloxone and morphine-insensitive binding of β-endorphin was extensively characterized on both murine splenocytes in culture and U937 cells, a human promonocytic cell line.10,11Our group reported that binding was saturable and sensitive to cations, guanosine triphosphate (GTP)-γS and incubation with phorbol myristate acetate.10-12 In contrast to neuronal opioid receptors, the β-endorphin binding site required the peptide's C-terminus (β-endorphin28-31) and N-acetyl β-endorphin was virtually equipotent to β-endorphin. Thus, both morphine and β-endorphin can bind to lymphoid cells through naloxone-insensitive sites that are distinctly different, atypical, and appear to modulate immune functions related to cellular proliferation.7,13,14

A limited number of radioligand binding studies have detected δ and κ opioid ligand binding to lymphocytes and other cells involved in host defense. Using [3H]deltorphin, binding to a single high affinity site (Kd = 0.45 nM) was observed on human peripheral blood polymorphonuclear leukocytes.15 Moreover, pretreatment with the irreversible ligand [D-Ala2, Leu5, Cys6]enkephalinamide (Dalce-NH2) differentially affected the binding of [3H]-deltorphin vs. [3H]-[D-Pen2, D-Pen5] enkephalin (DPDPE), suggesting that these cells express two types of δ-like opioid receptors. Other investigators have reported that macrophages and lymphocytes could be covalently crosslinked with δ selective ligands. Thus, labeling with cis(+)3-methylfentanylisothiocyanate (SUPERFIT) suggested the presence of δ-like opioid receptors on both B- and T-cell enriched murine splenocytes.16 Lymphoid cell lines have been used in binding studies with κ-selective ligands such as [3H]-U69,593. The murine R1.1 thymoma cell line showed a single high affinity site that bound [3H]-U69,593 or [3H]naloxone, and competition studies were consistent with expression of a κ opioid receptor (KOR).17 Data from additional experiments with cations or various guanylyl nucleotides were consistent with the presence of a neuronal KOR that coupled to a G protein.18 Taken together, these studies indicate the difficulty of detecting and adequately characterizing opioid receptors on normal immune cells using reversible radioligand binding. In contrast, cell lines have been used to describe classical neuronal KORs on cells derived from a murine thymoma.

Identification of Opioid Receptor Transcripts in the Immune System

Transcripts for μ, δ and κ opioid receptors have been detected on a variety of immune cells using primarily reverse transcription with polymerase chain reaction (RT-PCR). Initially, DOR mRNA was identified in simian peripheral blood mononuclear cells.19 Then, DOR transcripts were found in human T-, B- and monocyte cell lines and in some murine lymphocytic cell lines.20 Our group reported21 that the sequence of the PCR transcript amplified from 90% pure murine lymph node and splenic T-cells (Balb/c mice) was 98% identical with the murine DOR mRNA originally reported by Evans et al, in 1992.22 Freshly obtained murine splenocytes expressed very low transcript levels, and this was increased by culturing splenocytes without mitogenic stimulation.21,23 Using quantitative competitive RT-PCR amplification, we subsequently observed approximately 1 DOR transcript per T-cell in extracts prepared from fresh T-cell enriched populations (CD1 mice) that were 85% positive for Thy-1.24 Thus, the expression of murine DOR mRNA in mature T-cells does not appear to be strain-dependent.

Transcripts for μ and κ opioid receptors (MOR, KOR, respectively) have been identified by several laboratories. MOR was found in rat peritoneal macrophages and in human and simian peripheral blood mononuclear cells;25 in humans, monocytes, granulocytes and CD4+ T-cells were positive.26,27 KOR transcripts were also detected in human and monkey peripheral blood lymphocytes.26,27 In addition, immature thymic CD4, CD8 T-cells also express KOR mRNA.28

Regulation of DOR Transcript Expression

Amongst the three opioid receptor types, the regulation of DOR transcript expression has been studied most extensively. We observed that T-cell culture, in the absence of mitogens, increased transcript expression by 10- and 20-fold after 24 and 48 hours, respectively.24 In addition, DOR transcript expression increased linearly with increasing cell density when splenocytes were in culture for 48 h.23 To determine whether induction was dependent on the secretion of a soluble factor, supernatant transfer experiments were performed in which cells were cultured at relatively low density (1.2 × 10−6 cells/cm2) in medium containing supernatant from cells that previously had been cultured at either low or high density (3.0 × 10−6 cells/cm2). DOR expression was not enhanced by supernatants from cells cultured at high density.23 Therefore, direct T-cell cell interactions appear to mediate the enhanced expression of DOR mRNA by cultured splenocytes in the absence of mitogenic stimulation.

Stimulation by the T-cell mitogen, concanavalin A,29 or crosslinking the T-cell receptor (TCR) with anti-CD3-ϵ 24 enhanced the expression of DOR mRNA in murine CD4 T-cells. Using quantitative competitive PCR, our laboratory reported that anti-CD3-ϵ doubled the number of DOR transcripts per T-cell in comparison to the effect of culture alone.24 Thus, copy number increased from 10 (culture alone) to 22 and from 20 to 42 at 24 and 48 hours, respectively. In the presence of actinomycin D, anti-CD3-ϵ failed to alter the rate of transcript degradation (apparent half-life of 6 hours), suggesting that stability was unaffected.24 Hence, increased transcription appears to account for the anti-CD3-ϵ induced expression of DOR mRNA.

Phorbol myristate acetate (PMA) in the presence or absence of ionomycin affects DOR transcript expression in a manner opposite to that observed with anti-CD3-ϵ . We recently found that PMA alone or in combination with ionomycin inhibited the enhanced expression of T-cell DOR mRNA observed when splenocytes were cultured in the absence of mitogen.24 This was evident when T-cells were separated after splenocytes had been in culture for 24 and 48 hours. PMA also inhibited the anti-CD3-ϵ induced expression of DOR transcripts. Inspection of the mouse DOR gene promoter region revealed the presence of two sequences similar to the consensus TRE (phorbol esterresponsive element) and TRE-like elements. Although the function of these TRE domains has not been determined, studies have demonstrated that both of these elements mediate activation,30,31 as well as inhibition,32 of gene expression, depending on the cellular context. In a wide variety of cell types, phorbol esters have been shown to inhibit gene transcription. For example, PMA apparently inhibited transcription of the gene encoding the P2U-purinergic nucleotide receptor, a 7-transmembrane G-protein-coupled receptor expressed by HL-60 cells.33Since the activation of protein kinase C (PKC) apparently inhibits DOR gene expression, but anti-CD3-ϵ (an activator of PKC) has the opposite effect, it is possible that other TCR-dependent intracellular effectors deliver a dominant positive signal(s) resulting in enhanced DOR expression. The activation of PKC by PMA may shift this balance, perhaps reflecting that different isoforms of PKC are activated by PMA and/or the duration and magnitude of activation of PKC by PMA differs from anti-CD3e.

Identification of KOR and DOR by Indirect Fluorescence and Immunofluorescence Labeling

Using a high affinity κ agonist conjugated to fluorescein (FITCAA) and amplified with biotinylated anti-fluorescein IgG and extravidin-phycoerythrin, KOR were detected on murine thymocytes by fluorescence flow cytometry.34 More than 50% of the thymocytes positive for both CD4 and CD8 were KOR positive,35 and most of the thymocytes expressing KOR were of this phenotype. In contrast, murine splenocytes expressed KOR on less that 25% of freshly obtained CD4+ T-cells and 16% of B lymphocytes.36These findings suggest a decrease in KOR expression with T-cell maturation. In recent studies, Bidlack et al showed that mitogenic stimulation increased KOR expression by splenic T-cells in culture; this was especially evident on the CD8 subset.37

Recent studies from our laboratory have identified DOR on splenocytes by immunofluorescence, using epifluorescence microscopy with digital image analysis.38 Balb/c Vβ8.1 mice received a single injection of the superantigen staphylococcal enterotoxin B (SEB; which activates the TCR) and spleens were obtained at various time intervals, thereafter. SEB induced both DOR mRNA and enhanced immunofluorescence. Approximately 50% of the total T-cell population expressed DOR immunofluorescence within 15 hours of SEB treatment, compared to less than 10% of control T-cells. DOR expression was elevated for 24 hours, then gradually declined toward control levels by 72 hours. On a single cell basis, relative DOR immunofluorescence increased approximately twofold in a subpopulation of T-cells (26.8 +mn; 8.6 % of all T-cells) whose fluorescence intensity was greater than 2 standard deviations above the mean value of the corresponding control group. These studies demonstrate that DOR is expressed by T-cells in vivo through a TCR-dependent mechanism.

In recent flow cytometric studies, we have observed that phytohemagglutinin (PHA) stimulated the expression of DOR immunoflurescence by human peripheral blood T-cells.39 Approximately 50% of both the CD4 and CD8 T-cell subsets expressed DOR by 48 hours, and more than 90% of DOR was found on these cells. In additional experiments, the cell surface markers CD45RA and CD45RO were used to determine whether DOR is expressed by naïve or memory T-cells, respectively.39 These studies were performed 48 hours after stimulation by PHA, a time interval when the fraction of lymphocytes expressing CD45RA and CD45RO was unaffected by PHA. PHA stimulated similar fractions of both CD45RA- and CD45RO-positive T-cells to express DOR. Other studies (our unpublished observations) have shown that anti-CD3-ϵ induced the expression of DOR immunofluorescence by CD4 and CD8 T-cells obtained after splenocyte culture.

Opioid Receptor-Mediated Intracellular Signaling in the Immune System

In neuronal tissues, adenylyl cyclase is known to be inhibited by all three opioid receptor types. As it can be difficult to examine intracellular signaling with heterogenous populations of lymphoid cells, cell lines have been utilized by many investigators. The KOR expressed by the R1.1 thymoma cell line has been shown to inhibit basal and forskolin stimulate cAMP production in a pertussis toxin-sensitive manner, consistent with coupling to Gi proteins.40 Using a human T-cell line that stably expressed DOR (DORJu1.1), we also found that DADLE reduced forskolin-stimulated cAMP production by 70%, with an IC50 of 10−11 M, and this was sensitive to pertussis toxin.41 Finally, studies with human peripheral blood lymphocytes reported a biphasic effect of methionine enkephalin on intracellular cAMP concentrations: low concentrations (e.g., 10−12 M) elevated cAMP within 15 min, whereas nM concentrations reduced cAMP levels by 2 hours.42 Unfortunately, the effect of antagonists was not determined.

Several studies on the phosphorylation of the mitogen-activated protein kinases (MAPKs), extracellular-regulated kinases (ERKs) 1 and 2, have been reported in lymphoid cell lines. We and others reported that the DORs expressed by DORJu1.1 cells rapidly stimulate MAPK phosphorylation in a ras-independent manner.43,44 We also found that herbimycin A, a protein tyrosine kinase inhibitor, reduced the DADLE-induced phosphorylation of ERKs 1 and 2 by 70%.43 Furthermore, in CEMx174 lymphocytic cells, morphine stimulated the expression of proteins involved in the MAPK cascade and increased both the expression and phosphorylation of ERK 1 and 2.45 Thus, both MOR and DOR are coupled through, as yet undefined, pathways which activate ERK 1 and 2 in lymphoid cell lines.

The aforementioned findings differ from the effects of DOR (and MOR) on normal mature T-cells. Recently, DADLE was shown to inhibit anti-CD3-ϵ induced phosphorylation of ERKs 1 and 2 in murine splenic T-cells.38 Staphylococcal enterotoxin B was initially administered in vivo to stimulate the expression of DORs. Spleens were harvested 24 hours thereafter, and mixed splenocytes were preincubated with DADLE for 60 min and then stimulated with anti-CD3-ϵ for 5 min. In a concentration-dependent manner, we observed that DADLE (nM) reduced ERK phosphorylation by as much as 50%. The kinetics of anti-CD3-ϵ induced ERK phosphorylation were unaffected by DADLE, and DADLE alone did not alter ERK phosphorylation.38 Thus, DOR activation appears to inhibit anti-CD3-ϵ-induced ERK phosphorylation, rather than accelerating dephosphorylation of the ERKs. As noted, these observations differ from those made with DOR-transfected Jurkat T-cells (DORJu1.1), yet they fit well with a previous report showing that DADLE inhibited anti-CD3-ϵ-driven IL-2 production and proliferation of highly purified murine CD4 and CD8 T-cells. These inhibitory actions of DORs all require preincubation with DOR agonists prior to TCR crosslinking.


After more than two decades of intensive study, there is clear evidence from multiple laboratories for the existence and regulated expression of opioid receptors by cells involved in host defense and immunity. At both the protein and mRNA levels, there is especially good evidence for DOR and KOR on T-cells and other immune cells in several species. In the case of KOR, expression is greater in lymphoid compartments (e.g., thymus) that contain immature cells. However, both DOR and KOR expression are enhanced in activated cells. In addition, T-cells show enhanced DOR expression as a function of increasing cell density, independent of activation through the TCR. Although both MOR and DOR agonists can stimulate ERK phosphorylation in lymphoid cells lines, the opposite occurs in normal T-cells. These agonists alone do not affect ERK phosphorylation; however, following preincubation, they do inhibit anti-CD3-ϵ-induced ERK phosphorylation in splenic T-cells. Based on these observations, along with the antiproliferative effects of DOR agonists, DORs appear to be part of an inhibitory immunomodulatory system that can respond to both opioid neuro and immunopeptides secreted locally by innervating neurons and immune cells, respectively.


Our research is supported by PHS DA-04196.


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