Biomedical subjects

B Manfredi

Publications and source records attributed to B Manfredi.

At least 37 records · Page 2Linked to original sources

PubMed1997

Antinociceptive and immunosuppressive effects of opiate drugs: a structure-related activity study.

1. Although it is well known that morphine induces significant immunosuppression, the potential immunosuppressive activity of morphine derived drugs commonly used in the treatment of pain (codeine, hydromorphone, oxycodone) has never been evaluated. 2. We evaluated in the mouse the effect of the natural opiates (morphine and codeine) and synthetic derivatives (hydromorphone, oxycodone, nalorphine, naloxone and naltrexone) on antinociceptive thresholds and immune parameters (splenocyte proliferation, Natural Killer (NK) cell activity and interleukin-2 (IL-2) production). 3. Morphine displayed a potent immunosuppressive effect that was not dose-related to the antinociceptive effect, codeine possessed a weak antinociceptive effect and limited immunosuppressive activity; nalorphine, a mu-antagonist and kappa-agonist, exerted a potent immunosuppressive effect, but had very weak antinociceptive activity. The pure kappa-antagonist nor-BNI antagonized the antinociceptive, but not the immunosuppressive effect of nalorphine. 4. Hydromorphone and oxycodone, potent antinociceptive drugs, were devoid of immunosuppressive effects. 5. The pure antagonists naloxone and naltrexone potentiated immune responses. 6. Our data indicate that the C6 carbonyl substitution, together with the presence of a C7-8 single bond potentiates the antinociceptive effect, but abolishes immunosuppression (hydromorphone and oxycodone). 7. The single substitution of an allyl on the piperidinic ring resulted in a molecule that antagonized the antinociceptive effect but maintained the immunosuppressive effect. 8. Molecules that carry modifications of C6, the C7-8 bond and C14, together with an allyl or caboxymethyl group on the piperidinic ring antagonized both the antinociceptive and the immunosuppressive effect of opiates and were themselves immunostimulants.

Animals↗

PubMed1997

Intermittent but not continuous inescapable footshock stress and intracerebroventricular interleukin-1 similarly affect immune responses and immunocyte beta-endorphin concentrations in the rat.

Both CNS- and immunocyte(lymphocytes, splenocytes)-derived beta-endorphin is involved in immune responses to stress. We show in the rat that stress-induced immunodepression (decrease of mitogen-induced lymphocyte proliferation and NK activity) is present only after the administration of a stress paradigm that increases immunocyte-derived beta-endorphin, while this is absent when the concentrations of the opioid are not modified. Interestingly, plasma corticosterone levels were similarly elevated after stresses whether or not they suppress immune responses, thus suggesting a pivotal role of the opioid. The increase of immunocyte beta-endorphin and immunosuppression are similarly present also after the intracerebroventricular administration of interleukin 1, thus suggesting a role for this cytokine in stress responses. The modifications of immunocyte beta-endorphin concentrations and immune responses induced by stress and interleukin 1 are not affected by indomethacin, adrenalectomy or hypophysectomy, whereas they are completely blocked by a CRH antagonist and depletion of the serotoninergic or catecholaminergic systems. In conclusion, our results suggest that immune responses to stress are not uniquely linked to an activation of the HPA axis.

Animals↗

PubMed1996

Peripheral mononeuropathy affects hypothalamic and splenocyte beta-endorphin levels but not immune function in the rat.

Beta-endorphin and substance P levels were measured in the hypothalamus of rats 14 days after chronic constriction injury of right sciatic nerve. Furthermore, beta-endorphin concentrations in splenocytes, phytoemoagglutinin-induced proliferation of splenocytes, and natural killer activity were assessed. We observed a significant increase of beta-endorphin and substance P hypothalamic levels, and a significant decrease of beta-endorphin concentrations in the immune cells. In contrast, the peripheral mononeuropathy did not affect the immune function. This study presents a picture of central and peripheral peptide changes consistent with a painful condition, but different from what previously observed in rats which underwent peripheral nerve deafferentation or stressful conditions.

Animals↗

PubMed1996

Centrally injected nerve growth factor modulates peripheral immune responses in the rat.

The effect of the intracerebroventricular (icv) and intravenous (iv) injection of nerve growth factor (NGF) on peripheral immunity was studied in the rat. Icv administration of NGF (5, 25, 50, 250 and 500 ng/rat) significantly enhanced phytohemagglutinin (PHA)-induced splenocyte proliferation 30 min after treatment. Icv pretreatment with an anti-NGF antibody completely prevented the effect, while iv injection of anti-NGF antibody did not block the effect of icv NGF. On the contrary, NGF at doses of 0.5, 2.5, 5, 25 and 50 ng/rat decreased splenocyte natural killer (NK) activity. When injected iv, NGF enhanced splenocyte proliferation only at doses of 50 and 500 ng/rat, while it did not affect NK activity. These effects on immunity do not appear mediated by activation of the hypothalamus-pituitary-adrenal axis, since NGF did not modify plasma corticosterone concentrations at the doses used. These results indicate that NGF participates in the complex network of neuroimmune interactions.

Animals↗

PubMed1995

T-lymphocyte cholecystokinin-8 and beta-endorphin concentrations in eating disorders: I. Anorexia nervosa.

Baseline concentrations of cholecystokinin-8 (CCK-8) and beta-endorphin (beta-EP) were measured in T-lymphocytes from 33 restricting patients with anorexia nervosa (AN-R), 23 binging/purging patients with anorexia nervosa (AN-BP), and 24 healthy volunteers. CCK-8 basal values were significantly lower and beta-EP values significantly higher in AN-R and AN-BP patients than in normal volunteers. Levels of the peptides were measured three more times during a 4-month combined cognitive-behavioral/psychopharmacological treatment (nortriptyline or fluoxetine in AN-R, fluoxetine or amineptine in AN-BP). CCK-8 values fluctuated (nonsignificantly) during each treatment, while beta-EP values decreased (to a significant degree only in fluoxetine-treated AN-R patients).

Adolescent↗

PubMed1995

T-lymphocyte concentrations of cholecystokinin-8 and beta-endorphin in eating disorders: II. Bulimia nervosa.

Concentrations of cholecystokinin-8 (CCK-8) and beta-endorphin (beta-EP) in T-lymphocytes of 26 women with bulimia nervosa (BN) and in 26 age- and sex-matched healthy comparison subjects were measured. Ten patients were then treated with 300 mg/day of fluvoxamine, p.o., and five patients were treated with 300 mg/day of amineptine, p.o., for 4 months. Concentrations of the two peptides were measured again after 1, 2, and 4 months of therapy. Basal CCK-8 values were significantly lower in patients than in healthy subjects. During fluvoxamine therapy, CCK-8 values increased, reaching normal levels by month 4 of treatment. No such increase occurred during amineptine therapy. Baseline beta-EP values were normal in the bulimic patients but had declined by month 4 of fluvoxamine therapy.

Adolescent↗

PubMed1995

Plasma and synovial fluid interleukin-1, interleukin-6 and substance P concentrations in rheumatoid arthritis patients: effect of the nonsteroidal anti inflammatory drugs indomethacin, diclofenac and naproxen.

We performed an open, between patients, placebo controlled study in order to evaluate the effect of the treatment with the non steroidal anti inflammatory drugs indomethacin, diclofenac and naproxen on the concentrations of the cytokines IL-1 beta and IL-6 and of the neuropeptide substance P in plasma and synovial fluid of 24 rheumatoid arthritis patients. All patients had high synovial fluid cytokine and substance P levels, and high plasma cytokine levels at the beginning of the study. The treatment with the non steroidal anti inflammatory drugs significantly decreased both plasma and synovial fluid IL-6 and synovial fluid substance P in comparison to placebo, but did not affect IL-1 beta concentrations. This effect can participate in the therapeutic effect of non steroidal anti inflammatory drugs in rheumatoid arthritis.

Adult↗

PubMed1995

The beta-endorphin inhibition of mitogen-induced splenocytes proliferation is mediated by central and peripheral paracrine/autocrine effects of the opioid.

In this study we show that the opioid peptide beta-endorphin exerts a tonic inhibitory effect on the proliferative response of splenocytes to the polyclonal mitogen phytohemoagglutinin throughout two separate sites of action: one central and one peripheral. The intracerebroventricular administration of beta-endorphin, in fact, induces a significant inhibition of splenocyte proliferation. In contrast, both the intracerebroventricular and the peripheral administration of anti-beta-endorphin gamma globulins induce a significant increase in proliferation. Moreover, an increase of splenocyte proliferation was observed also after the intravenous administration of gamma globulins and intraperitoneal naloxone, and this effect was still present in hypophysectomized rats. The data reported suggest that beta-endorphin exerts a tonic inhibitory effect on proliferation, acting centrally, and peripherally throughout a paracrine/autocrine mechanism. FACS experiments show that the effect observed is not the consequence of an alteration of lymphocyte trafficking induced by the opioid.

Analysis of Variance↗

PubMed1995

Age-related changes in mitogen-induced beta-endorphin release from human peripheral blood mononuclear cells.

beta-Endorphin is an opioid peptide synthesized in the pituitary, hypothalamus, and immunocytes, known to affect immune responses both when added in vitro and when its synthesis is increased in vivo (e.g., during stress). We show here that, similar to its concentrations in peripheral blood mononuclear cells, the release of the opioid peptide from these cells after stimulation with polyclonal mitogens such as PHA or Con-A is also age dependent. Moreover, the effect of both mitogens on Ca2+ homeostasis changes with age. Finally, the ionophore ionomycin and the Ca2+ ATPase blocker thapsigargin induce the same age related effect on beta-endorphin release. For these reasons, we suggest that calcium homeostasis might be important for the differences observed in the release of the opioid from cells obtained from younger (< or = 30 years) or older (> or = 45 years) volunteers.

Adult↗

PubMed1995

Mitogen-induced lymphocyte proliferation and peripheral blood mononuclear cell beta-endorphin concentrations in primary dysmenorrhoea.

Dysmenorrhoea is a recurrent painful disease which causes physical and psychological stress. The purpose of the present study was to investigate whether there was a measurable derangement of immune cells and immune responses in women with severe primary dysmenorrhoea. On day 26 of one cycle and on days 1 and 3 of the following cycle we measured polyclonal, mitogen-induced lymphocyte proliferation and beta-endorphin concentration in peripheral blood mononuclear cells obtained from 16 infertile women with normal pelvis, of whom eight had and eight did not have the disorder. In women with dysmenorrhoea, polyclonal mitogen-induced lymphocyte proliferation was lower than in controls on all 3 days considered, but the difference was statistically significant only on day 26 (43,605 +/- 9876 micrograms/ml versus 67,305 +/- 15,249 micrograms/ml; P < 0.01). Monocyte beta-endorphin concentrations in the patients with dysmenorrhoea were significantly elevated on day 3 compared to controls (67.8 +/- 24.3 pg/10(6) cells versus 29.7 +/- 6.9 pg/10(6) cells; P < 0.05). Our results demonstrate that immune responses are modified in patients with primary dysmenorrhoea. These effects are independent of circulating hormone concentrations and are consistent with the role of dysmenorrhoea as a stressful event.

Adult↗

PubMed1994

Intermittent but not continuous inescapable footshock stress affects immune responses and immunocyte beta-endorphin concentrations in the rat.

It is well known that a variety of stressors influence immune responses. The opioid peptide-beta-endorphin (BE) is deeply involved in stress responses, is synthesized in cells of the immune system, and participates in the modulation of immune function. We analyzed the ability of two different stress paradigms to modulate the beta-endorphin concentrations in the immune cells and the immune response in the rat. Two and 24 h after the exposure to inescapable intermittent footshock (1.6 mA, 60 Hz, 1 s, every 5 s for 20 min) the concentrations of beta-endorphin in splenocytes, peripheral blood mononuclear cells and lymph node cells were significantly increased. In contrast, the exposure to a continuous footshock for 3 min did not affect the concentrations of the opioid peptide. Similarly, phytohemoagglutinin-induced proliferation of splenocytes and natural killer activity were significantly impaired only after the exposure to intermittent footshock stress. On the contrary, plasma corticosterone levels were similarly elevated after both paradigms of stress. The pretreatment with the corticotropin-releasing hormone (CRH) receptor antagonist prevented both the stress-induced increase of immunocyte BE and immunosuppression. In conclusion, our data suggest that intermittent and continuous footshock stressors activate different neuroendocrine responses and that CRH plays a central role in mediating the immune effects of the intermittent footshock stress. The possible relationship between the beta-endorphin changes and immunosuppression is discussed.

Acute Disease↗

PubMed1994

Beta-endorphin concentrations in brain areas and peritoneal macrophages in rats susceptible and resistant to experimental allergic encephalomyelitis: a possible relationship between tumor necrosis factor alpha and opioids in the disease.

Since the central nervous system and neuropeptides modulate immune functions, we investigated whether the different susceptibility of Lewis and Brown Norway rats to experimental allergic encephalomyelitis could also reflect differences in beta-endorphin and substance P concentrations in brain areas and macrophages during the development of the disease. We show that beta-endorphin concentrations increase much more in the hypothalamus and macrophages of Lewis rats during the development of the disease, while the increase is much lower or absent in Brown Norway rats. Tumor necrosis factor-alpha seems to play an important role in this difference. The administration of the opiate receptor antagonist naltrexone worsens the development of the disease, suggesting that the increase of the opioid beta-endorphin might represent a mechanism to downregulate the immune response. In both strains, the concentrations of substance P do not change.

Animals↗

PubMed1994

Beta-endorphin content in HIV-infected HuT78 cell line and in peripheral lymphocytes from HIV-positive subjects.

We investigated beta-endorphin (BE) content in an HIV-infected cell line and in peripheral blood mononuclear cells (PBM) from HIV-positive subjects. HIV infection increased BE content in HuT78 cell line compared to uninfected cells. Accordingly, BE content was greater in HIV-positive subjects than in healthy controls, both in fresh PBM and in mitogen-stimulated or unstimulated cultured cells. Further, in PHA-stimulated cultures, BE increase was correlated with disease progression. Opioids are known to decrease immune responsiveness in vivo, and it may be that the increased BE concentrations contribute to HIV-associated immune deficiency. In HIV-positive subjects, but not in healthy controls, intracellular BE concentration was positively correlated with PHA-induced PBM proliferation. The latter data suggest an alternative explanation: that the increased BE content represents a paradoxical response of the host in an attempt to balance virus-induced immunodepression. Thus, BE may be important in fine-tuning of the immune response with its up- and downregulation dependent upon differences in immune status.

Adult↗

PubMed1994

Intracerebroventricular interleukin-1 alpha increases immunocyte beta-endorphin concentrations in the rat: involvement of corticotropin-releasing hormone, catecholamines, and serotonin.

The opioid peptide beta-endorphin (BE) is synthesized and secreted by the cells of the immune system and has been shown to participate in the modulation of immune responses, e.g. during stress. Interleukin-1 (IL-1) is a potent activator of the corticotropin-releasing hormone (CRH) system in the hypothalamus, and it has been shown to be involved in many stress responses, including immunosuppression. We studied the effect of centrally injected IL-1 alpha on immunocyte BE concentrations in the rat. IL-1 alpha (1 ng/rat, intracerebroventricularly) significantly (P < 0.01) increased the concentrations of the peptide in splenocytes, lymph node cells, and peripheral blood mononuclear cells 2 and 24 h after treatment. Intracerebroventricular, but not iv, administration of 2 micrograms IL-1 receptor antagonist blocked the IL-1 alpha-induced increase. These effects were also prevented by the intracerebroventricular administration of the CRH receptor antagonist alpha-helical CRH-(9-41). Treatment with 6-hydroxydopamine and 5,7-dihydroxytryptamine, which deplete the catecholaminergic or the serotoninergic systems, respectively, blocked the increase in BE induced by the cytokine. In contrast, hypophysectomy and treatment with indomethacin did not modify the effect of IL. The increase in immunocyte BE, therefore, seems to depend on the activation of CRH, catecholamines, and serotonin, but to be independent of activation of the hypothalamus-pituitary-adrenal-axis and prostaglandins. The immunocyte BE increase could be involved in the immunosuppression induced by central IL-1 alpha.

Adrenalectomy↗

PubMed1994

Veralipride for hot flushes induced by a gonadotropin-releasing hormone agonist: a controlled study.

OBJECTIVES: To evaluate the efficacy of veralipride, a benzamide derivative, in the treatment of hot flushes induced by GnRH agonists (GnRH-a) and to study peripheral blood mononuclear cell beta-endorphin concentrations during drug administration. DESIGN: Randomized, placebo-controlled, double-blind trial. SETTING: Academic department of obstetrics and gynecology. PATIENTS: Forty women of mean age 43 +/- 5 years who experienced disturbing hot flushes during a 4-month course of tryptorelin depot for myoma-associated menorrhagia. INTERVENTIONS: Treatment with oral veralipride 100 mg/d (20 subjects) or matching placebo (20 subjects) during the third month of GnRH-a administration. MAIN OUTCOME MEASURES: Modifications of frequency and severity of hot flushes as shown by a 0 to 6-point vasomotor scoring system and variations of beta-endorphin levels in peripheral blood mononuclear cells. RESULTS: Two subjects in each group dropped out of the study. The median (range) vasomotor score at the end of the second month of treatment was 4 (3 to 6) in both the veralipride and placebo group. At the end of the third and fourth months the median (range) scores were, respectively, 2 (0 to 6) versus 4 (1 to 6) and 2 (0 to 5) versus 4 (1 to 6). No significant variations in mononuclear cell beta-endorphin concentrations were recorded. Serum PRL levels rose from 11.7 +/- 5.7 to 132.3 +/- 65.0 ng/mL (conversion factor to SI unit, 1.0) during veralipride administration and returned to 10.6 +/- 3.7 ng/mL after drug withdrawal. CONCLUSION: Veralipride reduced vasomotor symptoms induced by a GnRH-a. Transient hyperprolactinemia was the main side effect observed. The mode of action of the drug in GnRH-a-treated patients and possible interactions with endogenous opioid peptides need further elucidation.

Adult↗

PubMed1993

Evidence for an opioid inhibitory effect on T cell proliferation.

The proliferative response of human or rat T lymphocytes to phytohemagglutinin (PHA) or concanavalin A (ConA) was measured after acute (30 min) or chronic (8 days) treatment with the opiate receptor antagonists naloxone or naltrexone. Both in the rat and in the human, proliferation was significantly enhanced by acute treatment with the opiate receptor antagonists. In contrast, after chronic treatment proliferation always decreased. The sudden removal of an opioid inhibitory tone might be the basis for the increased proliferative responses observed after acute treatment. The decrease after chronic treatment could be ascribed to the amplification of the inhibitory effect of endogenous opioids due to the up-regulation of opiate receptors that follows chronic antagonist administration. Receptor binding studies of beta-endorphin receptors on splenocytes of chronically naloxone treated rats confirmed this hypothesis: a higher number of beta-endorphin receptors were expressed on splenocytes of naloxone-treated rats compared to controls (Bmax = 9.8 x 10(-12) vs. 1.16 x 10(-12), respectively).

Adult↗

PubMed1993

Psychoimmunoendocrine investigation in anorexia nervosa.

Immunological and neuroendocrine parameters were examined in 11 women with anorexia nervosa, 6 restricted and 5 bulimic-anorectics, 17-43 years old with 2-15 years duration of the disease, and in 11 age- and sex-matched psychophysically healthy controls. The T lymphocyte proliferative response to phytohemagglutinin (PHA), plasma adrenocorticotropic hormone (ACTH), cortisol and beta-endorphin (beta-EP) levels was examined in basal conditions and after corticotropin-releasing hormone (CRH) stimulation. Cortisol inhibition by dexamethasone (DST), and basal growth hormone (GH) and prolactin (PRL) levels were also examined. The immune study did not reveal significant differences between patients and controls. ACTH and cortisol basal levels were significantly higher in anorectics, while beta-EP, GH and PRL concentrations did not differ in the two groups. ACTH, beta-EP and cortisol responses to CRH were blunted in anorectics and the DST impaired in 55% of the patients. No correlations were observed between neuroendocrine impairments and the T lymphocyte response to PHA, or between the immunological neuroendocrine parameters and the body mass index of either patients or controls.

Adolescent↗

PubMed1992

Beta-endorphin concentrations in resting peripheral mononuclear cells and after treatment with PHA or serotoninergic drugs in human aging, Alzheimer's disease, and Down's syndrome.

We measured the concentrations of beta-endorphin in resting peripheral blood mononuclear cells obtained from normal subjects of different ages and from age-matched patients with Down's syndrome or Alzheimer's disease. We also measured beta-endorphin concentrations in peripheral blood mononuclear cells obtained from subjects of different ages after treatment with PHA or serotoninergic drugs. The results show that in normal subjects the concentrations of the peptide increase after 30 years of age and remain constant up to 99 years. After stimulation with PHA, the release of beta-endorphin in cells from subjects older than 30 years increases, leading to a decrease in contents, whereas it is unchanged in younger subjects. In patients with Down's syndrome or Alzheimer's disease, beta-endorphin concentrations in peripheral blood mononuclear cells behave similarly to those in age-matched normal subjects. Treatment in vivo with the serotoninergic agonist chlorimipramine induces an increase in beta-endorphin concentrations in peripheral blood mononuclear cells that is significantly greater in subjects over 30 years old than in younger subjects.

Adult↗