Opioids, opioid receptors, and the immune response

McCarthy, Lois E.; Wetzel, Michele A.; Sliker, Judith K.; Eisenstein, Toby K.; Rogers, Thomas J.

doi:10.1016/s0376-8716(00)00181-2

Cited by 364 publications

(252 citation statements)

References 105 publications

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“…The different types of opioid receptors have been defined based on pharmacological and radioligand-binding experiments, and more recently by cloning (25). The opioid receptors are located in varying densities throughout the central, peripheral, and autonomic nervous system as well as in several endocrine tissues and cells of the immune system (26,27). Endomorphins (endomorphin-1 and endomorphin-2) are endogenous opioid tetrapeptides that have been recently identified in the CNS and immune tissues with high selectivity and affinity for the -opioid receptor (28,29).…”

Section: Discussionmentioning

confidence: 99%

μ-Opioid Receptor Mediates Chronic Restraint Stress-Induced Lymphocyte Apoptosis

Wang

Charboneau

Barke

et al. 2002

The Journal of Immunology

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Psychological stress is associated with immunosuppression in both humans and animals. Although it was well established that psychological stressors stimulate the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, resulting in the release of various hormones and neurotransmitters, the mechanisms underlying these phenomena are poorly understood. In this study, μ-opioid receptor knockout (MORKO) mice were used to investigate whether the μ-opioid receptor mediates the immunosuppression induced by restraint stress. Our results showed that wild-type (WT) mice subjected to chronic 12-h daily restraint stress for 2 days exhibited a significant decrease in splenocyte number with a substantial increase in apoptosis and CD95 (Fas/APO-1) expression of splenocytes. The effects are essentially abolished in MORKO mice. Furthermore, inhibition of splenic lymphocyte proliferation, IL-2, and IFN-γ production induced by restraint stress in WT mice was also significantly abolished in MORKO mice. Interestingly, both stressed WT and MORKO mice showed a significant elevation in plasma corticosterone and pituitary proopiomelanocortin mRNA expression, although the increase was significantly lower in MORKO mice. Adrenalectomy did not reverse restraint stress-induced immunosuppression in WT mice. These data clearly established that the μ-opioid receptor is involved in restraint stress-induced immune alterations via a mechanism of apoptotic cell death, and that the effect is not mediated exclusively through the glucocorticoid pathway.

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Section: Discussionmentioning

confidence: 99%

μ-Opioid Receptor Mediates Chronic Restraint Stress-Induced Lymphocyte Apoptosis

Wang

Charboneau

Barke

et al. 2002

The Journal of Immunology

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“…Opioid absers have a higher incidence of infectious diseases, which may be directly related to impaired immune functions. [1][2][3][4][5][6] Opioids, such as morphine, exert a profound influence on immunomodulatory activity. The administration of morphine to rodents suppresses a variety of immune responses that involve the major cell types of the immune system, including natural killer cells, T cells, B cells, monocytes, macrophages, and polymorphonuclear leukocytes.…”

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confidence: 99%

Inhibition of Anti-HIV MicroRNA Expression

Wang

Zhou

et al. 2011

The American Journal of Pathology

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Several micro RNAs (miRNAs) have the ability to inhibit HIV replication in target cells. Thus, we investigated the impact of opioids (morphine and heroin), widely abused drugs among people infected with HIV, on the expression of cellular anti-HIV miRNAs in monocytes. We found that morphine-treated monocytes expressed lower levels of cellular anti-HIV miRNAs than untreated cells. In addition, morphine treatment of monocytes compromised type I interferon (IFN)-induced anti-HIV miRNA expression. These findings paralleled the observation that morphine treatment of monocytes enhanced HIV replication. These morphine-mediated actions on the anti-HIV miRNAs and HIV could be antagonized by the opioid receptor antagonists (naltrexone or Cys2, Tyr3, Arg5, Pen7-amide). Furthermore, the in vitro impact of morphine on miRNA expression was confirmed by the in vivo observation that heroin-dependent subjects had significantly lower levels of anti-HIV miRNAs (miRNA-28, 125b, 150, and 382) in peripheral blood mononuclear cells than the healthy subjects. These in vitro and in vivo findings indicate that opioid use impairs intracellular innate anti-HIV mechanism(s) in monocytes, contributing to cell susceptibility to HIV infection. (Am J

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“…Opioid and chemokine receptors are members of the Ga i protein-linked GPCR. These receptors and their ligands are expressed in neurons and glial cells, and in immune system cells such as lymphocytes, monocytes and neutrophils [7]. They share the same microenvironment in many physiological situations and are essential for inflammation processes.…”

mentioning

confidence: 99%

Ligand stabilization of CXCR4/δ‐opioid receptor heterodimers reveals a mechanism for immune response regulation

et al. 2008

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The CXCR4 chemokine receptor and the delta opioid receptor (DOR) are pertussis toxinsensitive G protein-coupled receptors (GPCR). Both are widely distributed in brain tissues and immune cells, and have key roles in inflammation processes and in pain sensation on proximal nerve endings. We show that in immune cells expressing CXCR4 and DOR, simultaneous addition of their ligands CXCL12 and [D-Pen2, DPen5]enkephalin does not trigger receptor function. This treatment does not affect ligand binding or receptor expression, nor does it promote heterologous desensitization. Our data indicate that CXCR4 and DOR form heterodimeric complexes that are dynamically regulated by the ligands. This is compatible with a model in which GPCR oligomerization leads to suppression of signaling, promoting a dominant negative effect. Knockdown of CXCR4 and DOR signaling by heterodimerization might have repercussions on physiological and pathological processes such as inflammation, pain sensation and HIV-1 infection.Supporting Information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2008/37630_s.pdf See accompanying article: http://dx.doi.org/10.1002/eji200738101 IntroductionThe G protein-coupled receptors (GPCR) represent the largest, most diverse family of transmembrane receptors expressed in the body. They act through G proteins to regulate intracellular processes including cell adhesion, migration and proliferation [1]. Studies show that the GPCR can function as oligomers [2,3]. Perhaps their most striking feature is that GPCR form not only functional homo-oligomers, but can also associate with other GPCR to form hetero-oligomers. Homo-and hetero-oligomers differ in their pharmacological pro- files, ligand binding affinity, and/or internalization pathways [4][5][6]. GPCR hetero-oligomerization would thus enable generation of new types of signaling units. Opioid and chemokine receptors are members of the Ga i protein-linked GPCR. These receptors and their ligands are expressed in neurons and glial cells, and in immune system cells such as lymphocytes, monocytes and neutrophils [7]. They share the same microenvironment in many physiological situations and are essential for inflammation processes. Chemokine receptors promote immune cell migration to and adhesion at the inflammation site, whereas opioid receptors reduce pain sensation on proximal nerve endings. Opioid receptors can also regulate the immune response, as they alter antibody responses, cell-mediated immunity, phagocytic activity, adhesion and chemotaxis [8][9][10][11]. Opioids also prevent leukocyte movement toward chemokine gradients [12], and cross-desensitization is described between opioid and chemokine receptors [8,10]. The CCR5 chemokine receptor can form heterodimers with each of the three opioid receptor subtypes (l, d, and j) [8,10].CXCR4, the most widely expressed chemokine receptor [13], is crucial for correct lymphocyte trafficking [14], hematopoiesis, and development [15][16][17]. It is also a coreceptor for T-tropic HIV strains [1...

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Opioids, opioid receptors, and the immune response

Cited by 364 publications

References 105 publications

μ-Opioid Receptor Mediates Chronic Restraint Stress-Induced Lymphocyte Apoptosis

μ-Opioid Receptor Mediates Chronic Restraint Stress-Induced Lymphocyte Apoptosis

Inhibition of Anti-HIV MicroRNA Expression

Ligand stabilization of CXCR4/δ‐opioid receptor heterodimers reveals a mechanism for immune response regulation

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