Abstract
Morphine is a widely used drug for analgesia and substance abuse. It has been accepted as a safe medication with great analgesic efficacy. Previous studies have reported that morphine is highly associated with the risk of immunosuppressive effects. Although the observed clinical effects suggest that morphine has the immunomodulatory capabilities, the mechanism of its action is still unclear. Here we review morphine on the bench to improve our understanding of the drug on the host immunity at the bedside. Studies of the effects of morphine on the innate and adaptive immune systems as well as immune responses are also discussed.
Keywords
adaptive immunity; analgesia; innate immunity; morphine;
1. Introduction
Morphine can be used for analgesia. Opiate drugs are widely prescribed drugs for pain management clinically. Despite its clinical efficacy for pain control, the common side effects of opiate drugs include nausea and vomiting1, 2, 3 due to a central action of morphine stimulating the part of the brain concerned with vomiting called the chemoreceptor trigger zone.4 The side effects of morphine on the other parts of the central nervous system are dependence leading to addiction,5 cough suppression,6, 7 and sedation.8, 9 Morphine can also induce histamine release, which causes itching of the skin and nose, and a mild flushing of the skin.1, 10 Nonetheless, as investigations of morphine continue, evidences suggest that morphine is highly associated with the risk of immunosuppression as revealed by both in vitro and in vivo studies.11, 12, 13, 14 Important investigations and studies are being pursued on the immunomodulatory effects of morphine on host immunity. Sabita et al15 reported that chronic morphine treatment in vivo could increase the Th2 differentiation of CD4+ T cells. In contrast to the activation of CD4+ helper T lymphocytes, the activity of CD8+ cytotoxic T lymphocytes was suppressed in the cellular immune response, when acute morphine was administered.16 Despite morphine has been studied on the immune responses in a lot of investigations, the mechanisms of how morphine influences the host immunity is still unclear. We will focus our attention on the effects of morphine on immunocytes to understand the possible mechanisms of this drug when being used clinically in patients with a wide variety of diseases.
2. Actions of morphine on the immune system
The immune mechanisms that occur in response to pathogens can be divided into the early immune response known as innate immunity. And the late immune response, which is specific is well-known as adaptive immunity. Studies have suggested that morphine has effects on both innate and adaptive immunities.
2.1. Innate immunity
The innate immunity is the immune system, which is the first line defense against infection. It includes a variety of cytokines and cells and mechanisms that defend the host from invasion of the body with organisms in a non-specific manner. Innate immunity can protect the host against a broad range of infections. In the mucosa of gastrointestinal tract, the innate immune system contributes to health and diseases through monitoring the enteric microbiota. Key participants in intestinal innate immune defenses are macrophages. Frenklakh et al17 first reported that macrophages isolated from mice receiving morphine demonstrated a greater apoptosis status than that of the control mice. The increasing macrophage injury by morphine can correlate with the degradation of the host defense barrier.17 Beside, morphine also affects the expression of innate immunity-related cytokines. Morphine can inhibit the secretion of various cytokines, which belong to the humoral component of innate immunity, including IL-1β, IL-2, and tumor necrosis factor alpha (TNF-α).
2.2. Regulation of phagocytosis
Phagocytosis is the process in which the cells swallow large particles, for example, as a pathogen crosses the epithelial barrier to enter host tissue. These foreign particles (pathogen) usually encounter host macrophages or neutrophils, which can recognize phagosize and then destroy the pathogens. However, studies showed that morphine could inhibit the phagocytotic activity of neutrophils18 and monocytes.19 Shirzad et al20 demonstrated a significantly decreased phagocytotic activity in animal with long-term morphine treatment. Tomassini et al21 further identified that opioid receptors μ and δ are essential for morphine-mediated inhibition of phagocytosis of peritoneal macrophages. Human monocytes treated with morphine also showed suppression of their phagocytotic activity.22 The mechanism by which morphine inhibited macrophage phagocytosis could be mediated by enhancing cyclic adenosine monophosphate expression.23 Besides, morphine can also stimulate the release of nitric oxide, which suppresses phagocytotic activity.18 There are several mechanisms such as NF-κB24 and P38 MAP kinase24 that might be involved in morphine-mediated phagocytotic inhibition.
2.3. Soluble immune mediators
A key mechanism to regulate innate immune system is to produce cytokines by immunocytes. Cytokines such as IL-1, IL-2, IL-6, and TNF-α play important roles in the pathogenesis of many immune-mediated diseases. Production of IL-2 by immunocytes is most important because it induces a variety of well-defined subsequent immune responses. Previous study also suggested that suppression of immune function by morphine could contribute to the disruption of cytokine expression including IL-2.25 The mechanism to suppress IL-2 expression in activated human T lymphocytes was that morphine could inhibit the activation of transcription factors AP-1, NFAT, and NF-κB,4, 26 which is essential for IL-2 trans-activation. In clinical studies, morphine-treated peripheral blood mononuclear cells also decreased the secretion of IL-2 and IFN-γ.23 These studies suggested that morphine can influence cytokine-mediated immune responses by the downregulation of IL-2.
The role of morphine in the influence on TNF-α has been investigated in numerous animal models and patients as well. Morphine can also reduce the production of TNF-α by mask cells27 and consequently decreases early peritoneal innate immunity responses.27 Chronic morphine treatment can decrease IL-1 and IL-6 expression.28 In infectious state, the lack of TNF-α, IL-1, and IL-6 expression will delay the recruitment of neutrophils, which increases the susceptibility for bacteria infection.28 One mechanism by which morphine inhibits the production of TNF-α is the suppression of extracellular signal-regulated kinase pathway.29 The inhibition of extracellular signal-regulated kinase pathway not only suppresses the host immunity but also enhances the tolerance in morphine treatment.29 Oppositely, morphine treatment has been reported to stimulate TNF-α secretion in HIV-associated nephropathic development.30 The increase of TNF-α will further stimulate nitric oxide generation, which promotes macrophage apoptosis.30 Taken together, morphine could act as an immunosuppressor in cytokine-mediated immunity.
2.4. Natural killer cells
The role of the innate immune system in regulating tumorigenesis is not only limited to soluble mediators but also includes immunocytes. Aside from macrophages, natural killer (NK) cells can also kill intracellular pathogens and tumor cells. Morphine suppresses NK cell activity has also been investigated in the animal model. The function of NK cells significantly decreased when treated the mice with morphine. However, the opiate antagonists naloxone and naltrexone could completely block the effect of morphine on NK cells and could also restore the function of NK cells.31 Morphine could inhibit NK cell-mediated cytolytic effects against breast cancer cells in rat model.32, 33 Clinical observation also demonstrated that the activity of NK cell decreased in surgical patients receiving morphine 24 h postoperatively.34 These studies indicated that morphine plays an important role in tumorigenesis by means of inhibiting the activity of NK cells.
2.5. Cell migration
The migration of leukocytes mediated by chemokine IL-8 is important for innate immunity because immunocytes can contact the foreign pathogens.35, 36 In the tumor microenvironment, neutrophils migrate to the site of invasion by means of chemotaxis, and this process is regulated by chemokine gradients including IL-8.31 The chemotaxis of neutrophils triggered by IL-8 has been reported to be suppressed by morphine.37 Morphine can inhibit the chemoattractant protein, CXCR-1, which is upregulated by IL-8. Lesser CXCR-1 expression in neutrophils after morphine treatment was also observed.38
Adhesion of leukocytes to the endothelium is another important issue for immunocytes migration and immunity.17 It requires the involvement of integrins family. Molecules including LFA-139 and Mac-13 of leukocytes may bind to the immunoglobulin-family adhesion proteins such as intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 on endothelium. Inflammatory stimuli, TNF-α, and IL-1 can induce the expression of ICAM-1. In vitro studies show that morphine can decrease both the expression of ICAM-1 and the adhesion of neutrophils.40 Morphine could further generate anti-inflammatory effects by reducing the adhesion of leukocytes to the extracellular matrix proteins. Evidences revealed integrins and chemokines can be involved in the compromising immunity.41, 42 TNF-α and monocyte chemoattractant protein-1 are two mediators of inflammation because they can stimulate leukocyte adhesion to extracellular matrix proteins.43 In addition to TNF-α, morphine can result in a significant inhibition of lipopolysaccharide-induced synthesis of monocyte chemoattractant protein-1.44 Miyagi et al45 revealed that morphine could interrupt chemokine-mediated immune functions in pathogen-mediated immunocytes migration. Overall, morphine can enhance cell adhesion-molecule–mediated adhesion in neutrophils to disrupt the host immunity. It seems that chemokines and opioids can interact and regulate host immunity. However, the detailed mechanism of morphine suppressing the host immunity by means of leukocyte migration needs further investigations.
3. Adaptive immunity
3.1. B cells
B lymphocytes play an important role in upregulating immune protein including the major histocompatibility complex class II (MHC II) molecules.46 The effects of morphine on B lymphocytes-mediated immunity and antibody production have mostly been studied in animal models. Morphine resulted in the reduction of B cells and macrophages in both spleen and peritoneal cavity.47 Subcutaneous injection of morphine can reduce the proliferative activity and the function of B cells in both the spleen and lymph nodes.48, 49 In vivo study also revealed that morphine could reduce the MHC II expression on the leukocytes, especially the B lymphocytes.50 Nugent et al51 also reported that morphine could also inhibit IL-4 upregulated MHC II gene expression. Besides, morphine could significantly inhibit the production of antigen-specific IgA and IgG. However, these phenomena could be rescued by the antagonist of opioid receptor, naltrexone.52 The studies indicated that morphine has a downregulatory effect on B cell-mediated immunity and antibody production. The possible mechanism can be the disruption of the expression of MHC II molecule and reduction of IL-4 secretion. And then these processes can inhibit the host immunity and increase the susceptibility to pathogenic infections.
3.2. T cells
T cells are divided into two broad classes depending on the expression of molecule on the cell surface: CD4 and CD8. The CD4+ T cells are known as T helper cells to act in assisting other white blood cells during the immunologic processes. The CD8+ T cells are known as cytotoxic T cells, which act on destroying virally infected or tumor cells. Morphine has been found to alter CD4+ and CD8+ subpopulations of T cells.13, 14 Both healthy individuals26 and patients receiving postoperative pain control53 when taking morphine, showed a decrease in the population of CD4+ T cells in their peripheral blood. Studies also showed that morphine can inhibit the proliferation of T cells in in vitro experiments.14, 54 One important mechanism to suppress the proliferation of T cells is to block T-cell receptor (TCR) signaling as well as co-receptor CD28 and/or co-stimulatory molecules (such as CD80 and CD86) on the activated antigen presenting cells. Studies have revealed that morphine could suppress T-cell-mediated immunity by means of inhibiting TCR signaling.48, 55 Besides, morphine could not only suppress the activation of TCR downstream signaling cascades MAPK, LAT, and Zap70 but also inhibit the phosphorylation of TCR initiating signaling molecule, Lck.55
The suppression of host immunity by inhibiting T-cell responses may be a mechanism of morphine-induced immunocompromise. While activation, naive CD4 T cells could differentiate into either T helper 1 (Th1) or T helper 2 (Th2) cells.56 Th1 cells are associated with superior cell-mediated and cytotoxic cell responses by secreting IFN-γ, whereas Th2 cells are associated with humoral immunity by secreting IL-4, IL-5, IL-6, IL-10, and IL-13.56 These cytokines can further stimulate and activate T cells. In the Th1-mediated immunity, morphine was found to decrease IFN-γ levels in anti-CD3/CD28-stimulated T cells57 or in DNA vaccination in in vivo experiments.13 In addition to IFN-γ-mediated Th1 immunity, IL-12 is another important cytokine that could regulate antigen-specific T-cell immunological response. Morphine combining with HIV-1 transactivating protein, Tat, has been demonstrated to induce the mRNA expression of inducible nitric oxide synthase27, CD40 ligand, IFN-γ-inducible protein 10, and the proinflammatory cytokines TNF-α and IL-1β.58 These observations can explain why morphine abusers with HIV infection have a global immune-compromised status.
IL-10 has also been reported to suppress Th1 cells maturation and activation in the development of Th1 cells.59 Sacerdote et al60 observed that mice receiving long-term morphine could significantly increase the production of IL-10 in the splenocytes. Besides, morphine can increase production of IL-461 and IL-562 and decrease IFN-γ production in HIV-1 infection patients’ peripheral blood mononuclear cells.44 Overall, these observations support the hypothesis that morphine can modulate Th1-mediated adaptive immunity, when in the situations of addiction or long-term use.
4. Conclusion
Morphine is a widely used drug for analgesia and substance abuse. It has been accepted as a safe medication with great analgesic efficacy. Previous studies reported that morphine is highly associated with the risk of immunomodulatory and immunosuppressive effects.11 The mechanisms underlying morphine-induced immunosuppression, although not well delineated, may include direct and indirect actions on the cellular immunity system.16, 45, 49 To focus on the influence of morphine on host immunity, morphine can alter mitogen-stimulated T and B-cell responses, attenuate antibody production, reduce NK cell activity, and suppress the proliferation and functions of T and B lymphocytes. Indeed, the impact of morphine use or morphine tolerance on cellular immunity remains to be elucidated. So much the better, should we understand the mechanism of morphine and its effects on immunity we can then provide a better use of this anesthetic drug in the clinical use.