Differential morphine tolerance development in the modulation of macrophage cytokine production in mice

Morphine has been shown to affect cell-mediated and humoral immune parameters. In this study, we investigated the capacity of in vivo acute and chronic morphine treatment to modulate interleukin (IL)-10 and IL-12 production by LPS and interferon-\u3b3-stimulated resident and thioglycollate-elicited murine peritoneal macrophages and the development of tolerance to these effects. One hour after the acute administration of 5, 10, and 20 mg/Kg morphine, a dose-related decrease of IL-10 and IL-12 levels was present. The pretreatment with naltrexone at doses up to 20 mg/Kg did not prevent the decrease of IL-10 and IL-12 induced by morphine. When the drug was administered chronically, a differential development of tolerance to the immune effects was observed. After 3 days of treatment, the effect of the acute challenge with 20 mg/Kg morphine on IL-12 was lost. In contrast, morphine-induced inhibition of IL-10 disappeared between 10 and 12 days of treatment, in parallel with tolerance to the antinociceptive effect. These results suggest that morphine treatment affects macrophage cytokine production and that tolerance affects this modulation differently

The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients

There has been growing interest in determining the possible immune consequences of opioid administration for the management of postoperative pain. We studied the effects of morphine and tramadol on pain and immune function during the postoperative period in 30 patients undergoing abdominal surgery for uterine carcinoma. Phytohemoagglutinin-induced T lymphocyte proliferation and natural killer cell activity were evaluated immediately before and after surgery, and 2 h after the acute administration of either 10 mg of morphine IM or 100 mg tramadol IM for pain. In all patients, phytohemagglutinin-induced lymphoproliferation was significantly depressed by surgical stress. However, in the morphine-treated group, proliferative values remained lower than basal levels for 2 h after treatment, whereas in tramadol-administered patients proliferative values returned to basal levels. Natural killer cell activity was not significantly affected by surgery nor by morphine administration, whereas tramadol significantly enhanced the activity of natural killer cells. Both drugs produced a comparable reduction in postoperative pain. We conclude that, as previously observed in the experimental animal, tramadol and morphine, when administered in analgesic doses, induce different immune effects

The opioid antagonist naloxone induces a shift from Type 2 to type 1 cytokine pattern in BALB/cJ mice

Opioid peptides affect different immune functions. We present evidence that these effects could be mediated by the modulation of T(H)1/T(H)2 cytokine production. BALB/cJ mice were immunized with 50 or 100 \u3bcg of the protein antigen keyhole-limpet hemocyanin (KLH), and treated acutely or chronically with the opioid antagonist naloxone. One and 2 weeks after immunization, the production of cytokines by splenocytes was evaluated by in vitro restimulation with KLH. The acute and chronic treatment with the opioid receptor antagonist naloxone decreased the production of interleukin (IL)-4 by splenocytes of BALB/cJ mice. In contrast, IL-2 and interferon-\u3b3 levels increased after naloxone treatment. Finally, the opioid antagonist diminished the serum immunoglobulin G anti-KLH antibody titers. These results suggest that naloxone increases T(H)1 and decreases T(H)2 cytokine production. The effect of naloxone could be ascribed to the removal of the regulatory effects exerted by endogenous opioid peptides, which could therefore activate T(H)2 and suppress T(H)1 cytokines. (C) 2000 by The American Society of Hematology

The analgesic drug tramadol prevents the effect of surgery on natural killer cell activity and mettastatic colonization in rats

Surgery stress has been shown to be associated in rat with decreased natural killer (NK) cell activity and enhancement of tumor metastasis. We have previously shown that the analgesic drug tramadol stimulates NK activity both in the rodent and in the human. In the present study, we analyze, in the rat, tramadol ability to prevent the effect of experimental surgery on NK activity and on the enhancement of metastatic diffusion to the lung of the NK sensitive tumor model MADB106. The administration of tramadol (20 and 40 mg/kg) before and after laparatomy significantly blocked the enhancement of lung metastasis induced by surgery. In contrast, the administration of 10 mg/kg of morphine was not able to modify this enhancement. The modulation of NK activity seemed to play a central role in the effect of tramadol on MADB106 cells. In fact, both doses of tramadol were able to prevent surgery-induced NK activity suppression, while the drug significantly increased NK activity in normal non-operated animals. Morphine, that in normal rats significantly decreased NK cytotoxicity, did not prevent surgery-induced immunosuppression. The good analgesic efficacy of tramadol combined with its intrinsic immunostimulatory properties suggests that this analgesic drug can be particularly indicated in the control of peri-operative pain in cancer patients

Social status in mice: behavioral, endocrine and immune changes are context-dependent

The aim of the present study was to investigate the effect of social status on the endocrine, immune and behavior response of male mice. We found that in mice reared in a group of siblings since weaning, no difference exists between dominants and subordinates in basal corticosterone level, in behavior in the open-field test (OFT) and in a series of immune parameters. These results suggest that living with siblings is not a stressful condition for either dominant or subordinate mice. Therefore, group-housed siblings can be regarded as a valid control group in social stress studies. When mice were subjected to chronic psychosocial stress for 21 days, four types of social outcome occurred: residents becoming dominants, intruders becoming subordinates, residents becoming subordinates and intruders becoming dominants. Interestingly, the behavioral profile in the OFT revealed a status-dependent effect, with resident dominants (RD) and intruder dominants (InD) showing the highest locomotor and exploratory activity, whereas the corticosterone level was higher than control for all four categories. In addition, a context-dependent effect emerged at the immune level: resident subordinates (RS) had a reduced splenocyte proliferation and IL-4 and IL-10 production. Mice in all the other three social ranks showed no immune alterations. Therefore, the loss of an individual's social rank position seems a promising field of study to investigate the psychological impact of stressful events

Chronic administration of UK-114, a multifunctional emerging protein, modulates the Th1/Th2 cytokine pattern and experimental autoimmune diseases

UK-114 is a 14-kDa ubiquitous protein recently sequenced by several groups throughout the world. Its activity ranges from being a tumor antigen, a protein synthesis inhibitor or a specific mu-calpain activator. UK-114 shows structural homologies also with proteins of the MHC-1 binding proteins, and heat shock proteins (HSPs). We investigated the possible effects of UK-114 on T helper cells cytokine profile and the development and progression of experimental autoimmune diseases. Homogeneous recombinant UK-114 was used in all experiments. Treatment of Balb/c male mice for two weeks resulted in the increase of IL-4, and the decrease of TNF-alpha, IFN-gamma, and IL-2 release from stimulated splenocytes, suggesting that UK-114 modulates the Th1/Th2 cytokine profile toward Th2. Similar to that observed with HSP60/65, a single pretreatment of Lewis rats with UK-114 significantly blunted the development of adjuvant-induced arthritis, whereas chronic treatment of 4-week-old female NOD mice dose dependently inhibited the development of diabetes