Iwona Filipczak-Bryniarska

The influence of opioids on the humoral and cell-mediated immune responses in mice. The role of macrophages

BACKGROUND Our experiments were aimed to test the influence of treatment with different opioids (morphine, fentanyl, methadone) on the humoral and cell-mediated immune responses. METHODS Mice were treated intraperitoneally (ip) with opioids for several days and next either immunized with sheep red blood cells (SRBC) to test the antibody production or skin-sensitized with hapten picryl chloride (PCL) to induce contact hypersensitivity (CHS). In addition, the effects of opioids on the production of reactive oxygen intermediates (ROIs) and cytokines by peritoneal macrophages (Mf) and on the expression of surface markers on these cells and blood leukocytes were estimated. RESULTS Opioids caused an enhancement of ROIs and cytokines production when macrophages were stimulated with zymosan or lipopolysaccharide (LPS) and reduced the expression of antigen presentation markers on Mf. Numbers of anti-SRBC plaque forming cells (PFC) and antibodies titres were lower in mice treated with all tested opioids. Depending on the use of particular opioid and the phase of allergic reaction, effects of the treatment on CHS were diverse. While morphine decreased the early and late phases of induction of CHS responses, methadone increased both reactions. In case of the effector phase of CHS, morphine and fentanyl increased both its early and late stages, while methadone decreased the late reaction. Treatment of recipients with opioids had diverse influence on the passive transfer of CHS in these animals. CONCLUSIONS Our experiments show that the action of opioids on the immune system is a complex phenomenon dependent on such variables as type of opioid, character of response (humoral versus cellular) and types of cells involved. Here Mf seem to play a significant role.

Repeatedly administered antidepressant drugs modulate humoral and cellular immune response in mice through action on macrophages

Depression is associated with an altered immune response, which could be normalized by antidepressant drugs. However, little is known about the influence of antidepressants on the peripheral immune response and function of macrophages in individuals not suffering from depression. Our studies were aimed at determining the influence of antidepressant drugs on the humoral and cellular immune response in mice. Mice were treated intraperitoneally with imipramine, fluoxetine, venlafaxine, or moclobemide and contact immunized with trinitrophenyl hapten followed by elicitation and measurement of contact sensitivity by ear swelling response. Peritoneal macrophages from drug-treated mice were either pulsed with sheep erythrocytes or conjugated with trinitrophenyl and transferred into naive recipients to induce humoral or contact sensitivity response, respectively. Secretion of reactive oxygen intermediates, nitric oxide, and cytokines by macrophages from drug-treated mice was assessed, respectively, in chemiluminometry, Griess-based colorimetry and enzyme-linked immunosorbent assay, and the expression of macrophage surface markers was analyzed cytometrically. Treatment of mice with fluoxetine, venlafaxine, and moclobemide results in suppression of humoral and cell-mediated immunity with a reduction of the release of macrophage proinflammatory mediators and the expression of antigen-presentation markers. In contrast, treatment with imipramine enhanced the humoral immune response and macrophage secretory activity but slightly suppressed active contact sensitivity. Our studies demonstrated that systemically delivered antidepressant drugs modulate the peripheral humoral and cell-mediated immune responses, mostly through their action on macrophages. Imipramine was rather proinflammatory, whereas other tested drugs expressed immunosuppressive potential. Current observations may be applied to new therapeutic strategies dedicated to various disorders associated with excessive inflammation.

In contrast to morphine, buprenorphine enhances macrophage-induced humoral immunity and, as oxycodone, slightly suppresses the effector phase of cell-mediated immune response in mice

Background Opioid receptors are commonly expressed on various immune cells, macrophages especially. Thus, these cells are prone to stimulation with opioids, which seems to be responsible for opioid‐induced immunomodulatory effects. While morphine, fentanyl and methadone influence on mouse immune response was recently studied, little is known about the potential immunomodulatory impact of buprenorphine and oxycodone. Aim The current research aimed to investigate the influence of buprenorphine and oxycodone on immune responses in mice under homeostatic conditions. Methods and results Repeated administration of morphine led to intensification of CHS response in actively sensitized mice, while buprenorphine or oxycodone administration exerted the opposite effect. Further, hapten‐conjugated macrophages from mice treated with morphine, when transferred into naive recipients, induced more potent CHS response. The enhanced generation of reactive oxygen intermediates and nitric oxide by macrophages from mice treated with buprenorphine, oxycodone or morphine was also shown, along with increased release of IL‐6, TNF&agr; and TGF&bgr;. Treatment with opioids altered expression of antigen phagocytosis and presentation markers. Finally, the inhibitory effect of morphine treatment on induction of humoral immunity by macrophages was demonstrated, while oxycodone failed to influence humoral immune response and buprenorphine actually enhanced B‐cell activation. Conclusions Current observations confirm that macrophages greatly contribute to immunomodulatory effects of opioids. Studies on immunomodulation by opioids have great importance related to the evaluation of its beneficial and adverse effects on patient condition. Our research showed that oxycodone exerts the weakest immunomodulatory properties, allowing us to assume this drug as safer than morphine during prolonged therapy. HighlightsMorphine treatment intensified CHS, while other opioids exerted opposite effect.All opioids stimulate reactive oxygen intermediate, NO and cytokine release.Morphine treatment inhibited, while buprenorphine enhanced B‐cell activation.Macrophages greatly contribute to immunomodulatory effects of opioids.Oxycodone exerts the weakest immunomodulatory properties.

Data supporting the understanding of modulatory function of opioid analgesics in mouse macrophage activity

The data presented herein expand the current understanding of the modulatory function of opioid drugs in mouse macrophage activity described in our relevant research article (Filipczak-Bryniarska et al., 2017) [1], in which we characterize the influence of morphine, buprenorphine and oxycodone on humoral and cell-mediated immune response in mice. Among other things, we have shown the effects of treatment with assayed analgesics on macrophage ability to induce antigen-specific B-cell response to sheep red blood cells as well as to generate reactive oxygen intermediates and nitric oxide. The current data demonstrate the effects of morphine, buprenorphine or oxycodone administration on phagocytosis of sheep red blood cells and zymosan by mouse macrophages, supplementing the data on immune modulatory capacities of assayed drugs, recently reported by us (Filipczak-Bryniarska et al., 2017; Kozlowski et al., 2017) [1,2].

Use of high-dose oxycodone hydrochloride in patients with visceral and neuropathic pain

1Department of Clinical Oncology, University Hospital in Krakow, Krakow, Poland 2Department of Experimental and Clinical Surgery, Jagiellonian University Medical College, Krakow, Poland 3Department of Palliative Medicine, Department of Internal Medicine and Geriatrics, University Hospital in Krakow, Krakow, Poland 4Department of Pain Treatment and Palliative Care, Jagiellonian University Medical College, Krakow, Poland 5Department of Oncology, Jagiellonian University Medical College, Krakow, Poland