PubMed Health⌕ Search

Biomedical subjects

D T Lysle

Publications and source records attributed to D T Lysle.

At least 55 records · Page 3Linked to original sources
PubMed1994

Pavlovian conditioning of morphine-induced alterations of immune status: evidence for opioid receptor involvement.

Prior work in our laboratory has shown that morphine's immunomodulatory effects can become conditioned to environmental stimuli that predict drug administration. These immune alterations include conditioned changes in natural killer cell activity, interleukin-2 production, and mitogen-induced lymphocyte proliferation. The present study examined the involvement of opioid receptor activity in the establishment and expression of conditioned morphine-induced alterations of immune status. During the training phase of the experiment, Lewis rats received two conditioning sessions during which a subcutaneous injection of 15 mg/kg morphine sulfate was paired with exposure to a distinctive environment. On the test day, animals were re-exposed to the distinctive environment alone prior to sacrifice. Saline or naltrexone (0.3, 1.0, 3.0 or 10.0 mg/kg) was administered during either the training or the test session. Administration of naltrexone prior to training antagonized the development of all of the conditioned alterations of immune status including changes in the mitogenic responsiveness of splenocytes, suppression of natural killer cell activity, and interleukin-2 production by splenocytes. Naltrexone administration prior to testing also was effective in antagonizing the expression of a subset of morphine-induced conditioned alterations in immune status. Taken together, these studies indicate that opioid receptor activity is involved in the establishment of conditioned morphine-induced immune alterations, as well as in the expression of a subset of these conditioned alterations of immune status.

Animals↗
PubMed1994

Evidence for the involvement of macrophage-derived nitric oxide in the modulation of immune status by a conditioned aversive stimulus.

Prior work in our laboratory has demonstrated that exposure to a conditioned aversive stimulus developed through pairings with electric shock results in pronounced alterations of immune status. These conditioned alterations of immune status include a decreased in natural killer cell activity, decreased production of interleukin-2 and gamma-interferon by concanavalin A (ConA)-stimulated splenocytes and a profound suppression of the mitogenic responsiveness of T and B lymphocytes to mitogens. The present study examines the role of macrophage-derived nitric oxide in the conditioned stimulus-induced suppression of lymphocyte proliferation by measuring the level of nitrite accumulation in culture, determining the effect of macrophage depletion, and assessing the effect of NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of the L-arginine-dependent nitric-oxide synthesizing pathway, alone and in combination with L- or D-arginine. The results show that the conditioned suppression of the mitogenic responsiveness of splenocytes to ConA is accompanied by a marked increase in nitrite accumulation. Both the depletion of macrophages and the addition of L-NMMA attenuates the conditioned suppression of ConA-stimulated lymphocyte proliferation. Furthermore, the addition of excess L-arginine, but not D-arginine, counteracts the effect of L-NMMA. The present findings show that the neuroendocrine alterations induced by a conditioned aversive stimulus suppress lymphocyte proliferation through alteration of the production of nitric oxide by macrophages.

Animals↗
PubMed1993

Alterations of immune status induced by the sympathetic nervous system: immunomodulatory effects of DMPP alone and in combination with morphine.

The aim of the present study was to explore the involvement of the sympathetic nervous system (SNS) in the immunomodulatory effects of morphine in Lewis rats and to assess the effects of alterations in SNS activity on immune status. In the first experiment, sympathetic tone was elevated by administering the ganglionic stimulant 1,1-dimethyl-4-phenylpiperazinium (DMPP) in doses of 0, 0.01, 0.1, and 1.0 mg/kg, sc, 5 min before the sc administration of 15 mg/kg morphine or saline. Animals were sacrificed 1 h after the morphine injection and multiple in vitro immune assays were then conducted. Although DMPP did not significantly enhance morphine's suppressive effects in the spleen and blood mitogen stimulation assays or the splenic natural killer (NK) cell assay, DMPP alone produced effects on immune status in saline-treated animals. Therefore, a second experiment was conducted to examine the immunomodulatory effects of increasing peripheral sympathetic outflow in greater detail. Animals were administered a wider dose range of DMPP (0, 0.005, 0.05, 0.5, and 5.0 mg/kg, sc) 30 min prior to sacrifice and an expanded repertoire of immune assays was conducted. DMPP dose-dependently suppressed the mitogenic responsiveness of splenic T lymphocytes, splenic NK cell activity, and interleukin-2 (IL-2) and gamma-interferon production by stimulated splenocytes. DMPP did not alter the total number of splenic leukocytes or the proliferative response of splenic B lymphocytes. In the mesenteric lymph nodes, DMPP had no effect on mitogenic responsiveness, the production of IL-2 or the total number of leukocytes. In the blood, however, DMPP increased mitogenic responsiveness at intermediate doses and decreased proliferation at higher doses. DMPP also dose-dependently decreased the number of blood leukocytes/ml. Taken together, these results indicate that increasing peripheral sympathetic outflow results in profound effects on immune status that depend upon the degree to which SNS activity is altered, the compartment of the immune system, and the lymphocyte subtype.

Adjuvants, Immunologic↗
PubMed1993

Genetic differences in social behavior: relation to natural killer cell function and susceptibility to tumor development.

The hypothesis that certain heritable personality traits would correlate with increased vulnerability to tumor development and reduced natural killer (NK) cell function was tested in mice selectively bred for high and low levels of aggression. This selection program produces a line of mice that fail to exhibit species typical, isolation-induced aggression, but appear socially inhibited in response to a novel partner mouse. All socially inhibited mice developed 3-methylcholanthrene-induced tumors compared with only 44% of the aggressive mice. Basal NK activity was also significantly lower among socially inhibited mice. Conversely, there were no line differences in NK activity between the aggressive line and nonselected, socially isolated mice, consistent with other unidirectional outcomes of this selective breeding program. No significant line differences were present for nonsocial measures of emotional reactivity (e.g., fearfulness) or serum corticosterone levels. These findings support the hypothesis that social "traits" may be related to immune function and tumor susceptibility.

Animals↗
PubMed1993

Morphine-induced alterations of immune status: dose dependency, compartment specificity and antagonism by naltrexone.

Although there is evidence to suggest that morphine can alter immune status, there is little information about the doses at which these effects occur, the extent of the immune alterations and whether morphine's immunomodulatory effects can be antagonized in a dose-dependent manner by an opioid antagonist. To address these issues, morphine (0, 5.0, 10.0, 15.0 or 25.0 mg/kg) was administered s.c. to Lewis rats. One hr later, the spleen, mesenteric lymph nodes and a sample of peripheral blood were collected. Immune status was assessed by a variety of in vitro assays. For splenic lymphocytes, morphine induced a dose-dependent suppression of lymphocyte function as measured by mitogen-induced proliferation, natural killer cell cytotoxicity, interleukin-2 production and interferon production. For blood lymphocytes, the mitogen-induced proliferative response was suppressed in a dose-dependent manner. In contrast, morphine did not alter the capability of lymphocytes in the mesenteric lymph nodes to proliferate or produce cytokines. In a separate study, naltrexone (0, 0.1, 1.0 or 10.0 mg/kg) was administered before the injection of morphine (15 mg/kg). The results show that the immunomodulatory effects of morphine are antagonized by naltrexone. Collectively, the results of this investigation show that morphine's immunomodulatory effects are dose dependent, compartment specific and antagonized by naltrexone.

Animals↗
PubMed1993

Evidence for beta adrenergic receptor involvement in the immunomodulatory effects of morphine.

The present study assessed the involvement of the beta adrenergic system in the immunomodulatory effects of morphine. Male Lewis rats were administered either the nonselective beta adrenergic antagonist nadolol, the beta 1-selective adrenergic antagonist atenolol or the beta 2-selective adrenergic antagonist erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylaminobuta n-2-ol (ICI-118,551) in doses of 0, 0.125, 0.5, 2.0 or 8.0 mg/kg s.c. before the administration of 15 mg/kg morphine or saline s.c. After sacrifice, the spleen was removed and blood was collected from each rat and multiple in vitro immune assays were performed. Pretreatment with all three beta adrenergic antagonists completely antagonized the suppressive effects of morphine on the proliferative responses of splenic leukocytes to concanavalin-A (Con-A), phytohemagglutinin (PHA), lipopolysaccharide (LPS) and the combination of ionomycin and phorbol myristate acetate (PMA). None of the antagonists blocked the suppressive effects of morphine on the proliferative responses of blood leukocytes to concanavalin-A or phytohemagglutinin, splenic natural killer (NK) cell activity, total splenic leukocyte counts and blood leukocyte counts per milliliter. These results demonstrate the involvement of beta adrenergic receptors in certain of morphine's immunosuppressive effects. Moreover, because both nadolol and atenolol are peripherally acting compounds, these data implicate peripheral beta adrenergic receptors specifically in morphine's immunomodulatory effects.

Animals↗
PubMed1992

Evidence for the involvement of beta-adrenergic receptors in conditioned immunomodulation.

This study investigates the role of beta-adrenergic receptors in the immunomodulatory effects of a conditioned aversive stimulus (CS). A CS is an environmental event that is not inherently aversive, but acquires aversive properties through pairings with a stimulus such as electric shock. This study evaluated the effects of administration of the beta 1-receptor selective antagonist atenolol, and the beta 2-receptor antagonist ICI 118,551 on conditioned immune alterations. Administration of either antagonist prior to presentation of the CS resulted in a dose-dependent attenuation of the CS-induced suppression of splenic T-cell proliferative response to concanavalin A, phytohemagglutinin, and the combination of ionomycin/phorbol-myristate-acetate. Furthermore, both antagonists dose-dependently attenuated the CS-induced suppression of gamma-interferon production by concanavalin-A (ConA)-stimulated splenocytes. In contrast, neither antagonist significantly attenuated the CS-induced suppression of the B-cell mitogenic response to LPS, interleukin-2 production, natural killer cell activity, or mitogenic responsiveness of blood lymphocytes. Thus it is likely that multiple mechanisms are involved in CS-induced immune alterations and these results clearly implicate beta 1 and beta 2-adrenergic receptors in a subset of immunomodulatory effects.

Adrenergic beta-Antagonists↗
PubMed1992

Pavlovian conditioning of morphine-induced alterations of immune status.

The present study provides the first demonstration that alterations of immune status can be conditioned to environmental stimuli paired with morphine administration. In the first manipulation, male Lewis rats received 0, 2, 4, 8 or 16 conditioning sessions during which a subcutaneous injection of morphine (15 mg/kg) was paired with a distinctive environment. The results showed that subsequent re-exposure to the distinctive environment induced a decrease in the mitogenic responsiveness of splenic lymphocytes and a decrease in natural killer cell activity in animals which had received 2, 4, 8 and 16 conditioning sessions. In the second manipulation, using two conditioning sessions, a wider range of immune measures was assessed and control groups were included to ascertain whether the observed immune alterations were due to Pavlovian conditioning processes. The results showed that the environment which had been paired with morphine altered the mitogenic responsiveness of blood and splenic lymphocytes, decreased natural killer cell activity and decreased interleukin-2 production. In contrast, the conditioned environment did not have any effect on mitogenic responsiveness of lymphocytes derived from the mesenteric lymph nodes. Data from the control groups revealed that the compartment-specific immune alterations were the result of a Pavlovian conditioning process.

Analysis of Variance↗
PubMed1992

Modulation of immune status by a conditioned aversive stimulus: evidence for the involvement of endogenous opioids.

Recent research has shown that presentations of an unconditioned aversive stimulus, such as electric shock, can induce alterations of immune function in rats. Furthermore, it has been demonstrated that an innocuous stimulus paired with an unconditioned aversive stimulus can acquire immunomodulatory properties. Research has suggested that endogenous opioid activity is responsible for the alterations of immune function by unconditioned aversive stimulation. The present study evaluated the effect of administration of opiate receptor antagonists, naltrexone and N-methylnaltrexone, on the immunomodulatory effect of a conditioned stimulus (CS) that had been paired with electric footshock. Naltrexone dose-dependently attenuated the CS-induced suppression of the in vitro proliferative response of splenic lymphocytes to concanavalin A, lipopolysaccharide, and a combination of ionomycin and phorbol myristate acetate. Naltrexone also attenuated the CS-induced reduction in natural-killer cell activity. In contrast, the quaternary form of naltrexone, N-methylnaltrexone, did not significantly attenuate the CS-induced immunomodulatory effects. Collectively, these findings indicate that endogenous opioid activity is involved in CS-induced alterations of immune function. Moreover, the lack of effectiveness of N-methylnaltrexone in attenuating the CS-induced immunomodulatory effect suggests that the opioid receptors involved in the effect are located in the central nervous system.

Animals↗
PubMed1992

Suppression of the development of adjuvant arthritis by a conditioned aversive stimulus.

The present study evaluated the effect of a conditioned aversive stimulus (CS) on the development of adjuvant-induced arthritis in Lewis rats. Experiment 1 showed that presentation of a CS, on days 12, 14, and 16 following injection with adjuvant containing mycobacterium tuberculosis, resulted in a pronounced suppression of the development of arthritis as measured by a clinical disease severity rating scale and spleen weight. In contrast, presentation of the CS on days 0, 2, and 4 following injection did not have any effect on the development of arthritis. Experiment 2 showed that the suppression of adjuvant arthritis by exposure to the CS was blocked by administration of propranolol, a nonselective beta-adrenergic receptor antagonist. These results demonstrate that a CS can alter the development of adjuvant-induced arthritis, but the effect is dependent upon the timing of the antigen exposure and the presentation of the CS. Moreover, the present findings suggest that blocking beta-adrenergic receptors during presentations of the CS prevents the suppressive effect of the CS.

Animals↗
PubMed1991

Stressor-induced changes in mitogenic activity are not associated with decreased interleukin 2 production or changes in lymphocyte subsets.

Splenic lymphocytes from Lewis rats that received presentations of physically aversive electric shock demonstrated a marked reduction in responsiveness to T-cell mitogens such as concanavalin A. This study examined cellular mechanisms which may be responsible for this functional alteration. There was no difference in distribution of T-cell subsets from shocked and nonshocked rats. There was no difference in the production of interleukin 2 (IL-2) nor was there a difference in the percentage of IL-2 receptor positive T cells or T-cell subsets after culture for 24 hr. However, there was a marked lack of mitogenic stimulation in splenocytes from shocked rats when stimulated with the calcium ionophore A23187. This indicates a defect in the biochemical pathways necessary to activate T-cell mitogenesis.

Animals↗
PubMed1991

Pharmacological manipulation of immune alterations induced by an aversive conditioned stimulus: evidence for a beta-adrenergic receptor-mediated Pavlovian conditioning process.

The effect of propranolol, a beta-adrenergic receptor antagonist, on the suppression of splenic mitogenic responsiveness induced by an aversive conditioned stimulus (CS) was evaluated in rats. Experiment 1 demonstrated that propranolol administration before presentation of the CS completely blocked the suppressive effect. In contrast, Experiment 2 showed that administration of propranolol during the training of the aversive CS had no effect on the suppressive effect of the CS in a subsequent test. These findings indicate that the release of catecholamines is responsible for the conditioned immune alteration of splenic lymphocytes. Taken further, these findings suggest that the learning of the conditioned immunomodulatory response to an aversive CS is a Pavlovian conditioning process that is not dependent on the performance of the conditioned response during training.

Adjuvants, Immunologic↗
PubMed1990

Evidence that shock-induced immune suppression is mediated by adrenal hormones and peripheral beta-adrenergic receptors.

Our previous work has demonstrated that presentations of mild foot-shock to Lewis rats induces a suppression of splenic and peripheral blood lymphocyte responses to nonspecific T-cell mitogens. The present study demonstrated that adrenalectomy prevented the shock-induced suppression of the mitogenic response of peripheral blood T-cells but did not attenuate the suppression of splenic T-cells. Conversely, the beta-adrenergic receptor antagonists, propranolol and nadolol, attenuated the shock-induced suppression of splenic T-cells in a dose-dependent manner but did not attenuate suppression of the blood mitogen response. These data indicate that distinct mechanisms mediate the shock-induced suppression of T-cell responsiveness to mitogens in the spleen and the peripheral blood. The results indicate that the peripheral release of catecholamines is responsible for splenic immune suppression and that adrenal hormones, which do not interact with beta-adrenergic receptors, are responsible for shock-induced suppression of blood mitogenic responses.

Adrenal Cortex Hormones↗
PubMed1990

Immobilization 12 days (but not one hour) earlier enhanced 2-deoxy-D-glucose-induced immunosuppression: evidence for stressor-induced time-dependent sensitization of the immune system.

1. Prior exposure to a stressor can either increase or decrease subsequent behavioral, neurochemical, and endocrine reactivity to stress, depending on the pattern of stress exposure. 2. Massed or frequent exposures typically induce a reduction in reactivity whereas intermittent or widely spaced exposures increase subsequent reactivity. 3. In the present study, the authors examined whether a single presentation of a temporally remote stressor would increase the immunosuppressive effects of a subsequent stressor. Specifically, the authors investigated the effectiveness of 2-deoxy-D-glucose (2-DG) in suppressing the responsiveness of splenic lymphocytes in male, Sprague-Dawley rats that received either no prior treatment, or immobilization either one hour or 12 days earlier. 4. Splenic lymphocyte responsiveness to the T-cell mitogens, Concanavalin A (Con-A) and phytohemagglutinin (PHA) was suppressed following a single injection of 2-DG. 5. The group exposed to the stress of immobilization one hour prior to 2-DG demonstrated a comparable level of immune suppression. 6. In contrast, animals immobilized 12 days prior to the administration of 2-DG showed a more pronounced suppression of immune responsiveness which was significantly greater than the other groups injected with 2-DG. 7. Neither the stress-induced elevation in corticosterone, nor the suppression of blood lymphocyte reactivity to Con-A and PHA was enhanced by prior immobilization. 8. The results indicate that the immunosuppressive effects of an acute stressor can sensitize with the passage of time.

Animals↗
PubMed1990

Stressor-induced alteration of lymphocyte proliferation in mice: evidence for enhancement of mitogenic responsiveness.

The present study evaluated the immunomodulatory effect of the administration of different intensities of electric foot shock presentations to different strains of mice. The results showed an enhancement of the mitogenic responsiveness to concanavalin A (Con A), a T-lymphocyte mitogen, that was directly related to the intensity of the electric shock presentations. However, the electric shock induced no significant alteration of the mitogenic responsiveness to lipopolysaccharide (LPS), a B-lymphocyte mitogen. These findings were evident in HLA-SW/ICR, C57BL/6N, and C3H/HEJ mice. In contrast, the C3H/HEN mice did not show any alteration of mitogenic responsiveness. The number of splenic leukocytes was not altered by the electric shock presentations in the strains that showed enhanced mitogenic responsiveness, but the C3H/HEN strain showed a leukopenia directly related to the shock intensity. In a subsequent experiment, it was demonstrated that repeated sessions of electric shock resulted in a reduction in the enhancement effect. Collectively, the results demonstrate that stressful stimulation can result in an enhancement of mitogenic responsiveness, but that such an effect is dependent on the intensity and frequency of the stressor, as well as on the strain of the subject.

Animals↗