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PubMed1994

Enhanced susceptibility of the immune system to stress in morphine-tolerant rats.

The purpose of the present study was to determine the potential consequences to the immune system of the combined exposure of rats to stressor and morphine. Within 30 min following either morphine (5 mg/kg) injection or restraint stress (30 min) maximal analgesic responses as measured by tail-flick assay were observed. However, only morphine treatment was accompanied by a significant suppression (50%) in mitogen-stimulated lymphocyte proliferative responses. Restraint stress for either a 30-min or 2-h duration had no effect on lymphocyte responses. Exposure to a combination of restraint stress and acute morphine (5 mg/kg) resulted in a 50% suppression of lymphocyte responses which was similar in magnitude to that observed with morphine administration alone. When rats were injected twice daily for 4 days with increasing doses of morphine ranging from 10 mg/kg to 40 mg/kg, morphine (10 mg/kg) administration on Day 5 was not accompanied by either analgesia or depressed blood lymphocyte proliferative responses. These results indicated that tolerance had developed to both the analgesic and the immunosuppressive effects of morphine. However, upon exposure of morphine-tolerant animals to restraint stress, significant analgesic responses were retained. Furthermore, in contrast to the lack of suppression following restraint stress on lymphocyte responses in saline-injected animals, restraint for 30 min produced greater than a 70% suppression in morphine-tolerant animals. These data suggest that morphine tolerance may be accompanied by an enhanced susceptibility to the immunosuppressive effects of stress.

Analgesia↗
PubMed1994

Chronic morphine treatment suppresses CTL-mediated cytolysis, granulation, and cAMP responses to alloantigen.

Exposure to opioid drugs (e.g., morphine) in vivo has been shown to suppress natural killer cell activity. However, the effects of in vivo exposure to opioids on cytotoxic T lymphocyte (CTL) activity has not been investigated. The administration of morphine (50.0 mg/kg, sc) to alloimmunized mice for 11 days resulted in a significant decrease in peritoneal and splenic CTL activity. Moreover, the intracellular content of serine esterases and esterase release by CD8+ effector cells from chronic morphine-treated mice was reduced compared to that of effector cells from vehicle-treated controls. In addition, the CD8+ cAMP response to alloantigen was diminished compared to CD(8+)-enriched cells from vehicle-treated animals. However, conjugate formation between effector and target and subsequent killing of target by effector cells did not reveal significant differences between vehicle- and chronic morphine-treated animals. Serum corticosterone and dehydroepiandrosterone levels were significantly lower in the chronic morphine-treated animals while proopiomelanocortin gene expression (exon 3) in splenic lymphocytes did not correlate with morphine-mediated suppression of CTL activity. These results indicate that CTL activity is sensitive to chronic morphine exposure, implicating opioids as important cofactors during viral infections in suppressing cell-mediated immunity.

Animals↗
PubMed1994

Pavlovian conditioning of morphine-induced alterations of immune status: evidence for peripheral beta-adrenergic receptor involvement.

The present studies examined the involvement of peripheral beta-adrenergic receptor activity in the establishment and expression of conditioned morphine-induced alterations of immune status. Previous work in our laboratory has shown that morphine's immunomodulatory effects can become conditioned to environmental stimuli which predict drug administration. These immune alterations include conditioned changes in natural killer cell activity, interleukin-2 production, and mitogen-induced lymphocyte proliferation. During the training phase of these experiments, 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, rats were reexposed to the conditioned stimulus prior to sacrifice. Saline or nadolol (0.002, 0.02, 0.2, or 2.0 mg/kg) was administered either prior to the training sessions or prior to the test session. Administration of nadolol prior to training did not affect the development of conditioned alterations of immune status. Conversely, nadolol administration prior to testing completely attenuated the expression of a subset of the conditioned morphine-induced changes in immune status. Taken together, these studies suggest that whereas peripheral beta-adrenergic receptor activity is not required for the establishment of conditioned morphine-induced alterations of immune status, it is involved in the expression of a subset of these conditioned immunomodulatory effects.

Animals↗
PubMed1994

Electrical stimulation of the dorsal midbrain periaqueductal gray suppresses peripheral blood natural killer cell activity.

This study examined the effects of dorsal midbrain periaqueductal gray (PAG) stimulation on both splenic and peripheral blood natural killer (NK) cell function as well as the proliferative response of lymphocytes to phytohemagglutinin mitogen. Male Sprague-Dawley rats were implanted with bipolar electrodes in the dorsal PAG. Following recovery, bipolar electrical stimulation eliciting a flight response was delivered at the rate of one/min for 30 min to freely moving rats. While dorsal PAG stimulation did not alter mitogen response or splenic NK activity, stimulation of this region of the PAG produced a marked decrease in peripheral blood NK response. In order to begin to explore a possible mechanism regulating suppression of peripheral blood NK activity, naltrexone (10 mg/kg) was administered prior to dorsal PAG stimulation. The results of this experiment replicated the findings that demonstrated suppression of peripheral blood NK following dorsal PAG stimulation. Naltrexone did not effect PAG induced suppression of peripheral blood NK. These findings point to the importance of the dorsal aspect of the PAG in the regulation of peripheral blood NK activity and further suggest that this phenomenon may not be opioid mediated.

Animals↗
PubMed1994

Both T cells and macrophages are targets of kappa-opioid-induced immunosuppression.

We have previously shown that antibody responses are inhibited following administration of kappa-opioid agonists. We found that the inhibition was blocked by either naloxone or the kappa-selective antagonist norbinaltorphimine. This inhibitory activity is apparent after short-term treatment with the kappa-opioid agonist. In an attempt to identify the cell populations which serve as the target for this immunosuppressive effect, we have carried out cell fractionation analyses to generate isolated T cells and macrophages. Using multiple cell fractionation methods, we have determined that short-term treatment of either T cells or macrophages with the kappa-opioid agonist U50,488H results in significant inhibition of in vitro antibody responses. We also find that the inhibition of both T cell and macrophage activity can be blocked by naloxone. These studies demonstrate that resting T cells and macrophages express kappa-opioid receptors and exhibit significant opioid responsiveness prior to activation by antigen.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1994

The role of LGL/NK cells in surgery-induced promotion of metastasis and its attenuation by morphine.

Painful stress such as surgery has been shown both to suppress immune function and to promote metastasis, although the degree to which alterations in immunity underlies the tumor-enhancing effects of surgery remains unclear. We recently reported that an experimental laparotomy results in a twofold increase in the number of lung metastases following iv injection of MADB106 tumor cells, a natural killer (NK)-sensitive mammary adenocarcinoma cell line, syngeneic to the Fischer 344 rats we studied. Further, the administration of an analgesic dose of morphine prevented these metastatic-enhancing effects of surgery. The aim of the present study was to investigate the role of NK cells in both the metastatic-enhancing effects of surgery and the attenuation of these effects by morphine. Using a simple 2 x 2 experimental design (surgery with anesthesia vs anesthesia only, and morphine vs vehicle), we found that surgery resulted in a decrease in both whole blood NK cytotoxic activity and number of circulating LGL/NK cells assessed 4 h postoperatively. In a second experiment involving an 18-h lung clearance assay, we used the mAb 3.2.3 to deplete rats of LGL/NK cells with the following rationale: if LGL/NK cells are necessary to mediate an event, then in their absence, that event should not occur. Normal and LGL/NK-depleted animals were assigned to the same four experimental groups, and radiolabeled MADB106 tumor cells were injected iv 4 h after surgery. In normal animals, there was a significant interaction between surgery and morphine such that morphine attenuated the surgery-induced increase in tumor cell retention without affecting tumor cell retention in the anesthesia groups. In the LGL/NK-depleted animals, however, although the tumor-enhancing effects of surgery remained evident, morphine did not mitigate this outcome. These results suggest that: (a) both LGL/NK cell activity and other factors independent of LGL/NK cells play a role in the surgery-induced increase in tumor cell retention; and (b) LGL/NK cells play a critical role in morphine's attenuating effects on this outcome. Finally, these results reinforce concern about the pathogenic consequences of unrelieved pain.

Adenocarcinoma↗
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↗
PubMed1995

Suppressed T cell and macrophage function in the "reeler" (rl/rl) mutant, a murine strain with elevated cerebellar norepinephrine concentration.

The effects of neurochemical alterations in specific brain regions on the immune system were examined in reeler (rl/rl) mice, a neurologic mutant strain having an abnormally high concentration of cerebellar norepinephrine (NE). Following immunization with sheep red blood cells, lower numbers of IgM-producing B cells were found in rl/rl mice than in B6C3Fea/a controls. Interleukin-1 (IL-1) production by splenic macrophages from rl/rl mice was reduced compared to B6C3F3a/a controls, as was the proliferative response of splenic T lymphocytes from rl/rl mice activated with an anti-CD3 monoclonal antibody. Levels of IL-4, interferon-gamma and IL-2 produced by splenic T lymphocytes from rl/rl mice were also lower than those of B6C3Fea/a controls. Rl/rl mice do not have an intrinsic defect in the ability to produce IgM, as lipopolysaccharide activated splenic lymphocytes from rl/rl mice produced levels of IgM similar to those of controls. This suggests that defective function in the T lymphocyte and/or macrophage population rather than in the B cell population may underlie the defect in IgM production. No significant alterations were observed in basal splenic levels of NE or neuropeptides in rl/rl mice relative to controls. The reeler mouse model shows that alterations in immune function are present in a strain with inherited alterations in cerebellar noradrenergic innervation and NE concentration.

Animals↗
PubMed1995

Altered thyrotropic and somatotropic responses to environmental challenges in congenitally athymic mice.

Neonatal thymectomy or congenital absence of the thymus induces morphologic alterations in pituitary somatotrophs as well as in thyroid epithelium. It was therefore of interest to assess somatotropic and thyrotropic cell morphology and the corresponding serum hormone levels in athymic nude mice under basal and stressful conditions, taking as a reference their haired counterparts. Normal (+/+), heterozygous nude (nul+) and homozygous (nu/nu) CD-1 mice were subjected to either 1-h immobilization stress or 2-h cold stress. Serum levels of growth hormone (GH), thyrotropin (TSH), thyroxine (T4), and triiodothyronine (T3) were assessed by RIA at 0, 30, and 60 min poststress. Athymic animals showed lower basal levels of serum TSH, GH, and T3, but not T4, than their heterozygous littermates. Immunohistochemical assessment of somatotropic and thyrotropic cell populations revealed a normal morphology in the athymic animals. Immobilization stress induced a marked reduction in GH and TSH levels in normal mice but had only a weak effect in athymic animals. Two hours of cold exposure caused a comparable increase in serum TSH in normal and athymic animals, whereas the serum T4 and T3 response to cold was greater in the athymic nudes. Cold exposure drastically reduced serum GH levels in normal animals but had only a weak effect in the athymic mice. We conclude that congenital athymia in the mouse is associated with decreased basal levels of serum TSH and GH in the presence of a normal somatotroph and thyrotroph morphology. The anomalous responses of athymic mice to stress do not appear to be due to primary hypopituitarism but rather, to an altered modulation of pituitary hormone secretion.

Animals↗
PubMed1995

Naloxone exacerbates intestinal and systemic anaphylaxis in the rat.

Following sensitization to ovalbumin (OA), male Wistar rats were pretreated with naloxone (20 mg/kg i.p.) and subjected to antigen challenge (3 mg OA i.p.). Naloxone exacerbated both systemic and intestinal anaphylaxis when injected 10 and 90 min before the antigen challenge. This was evidenced by a more pronounced drop in rectal temperature, higher hematocrit values, and by an enhanced elevation of basal short-circuit current (an indication of the secretory tone of the small intestine studied in Ussing chambers). Pretreatment with an equipotent does of methylnaloxone (200 mg/kg i.p.), a peripherally acting opiate antagonist, exacerbated the indices of intestinal anaphylaxis but had no apparent effect on indices of systemic anaphylaxis. Thus, our data strongly suggest that in the rat, components of the systemic hypersensitivity reaction are mediated through central opioid receptors, whereas the changes in gut function characterizing intestinal anaphylaxis are mediated through peripheral opioid receptors.

Anaphylaxis↗
PubMed1995

Stressed rats fail to expand the CD45RC+CD4+ (Th1-like) T cell subset in response to KLH: possible involvement of IFN-gamma.

Exposure to stressors effects various aspects of immune function, including the in vivo antibody response. We have previously reported that rats exposed to an acute session of inescapable tail shock (IS) show long-term reductions in anti-KLH (keyhole limpet hemocyanin) IgM and IgG. The mechanisms responsible for this suppression are currently unknown. Previous work has suggested changes in CD4+ T cells could be important. We report here that exposure to IS results in a reduction in Con A-stimulated IFN-gamma levels in mesenteric lymphocytes and splenocytes taken immediately after IS termination. In addition, IS exposure prevents the KLH-induced increase in the number of CD45RC+CD4+ T cells (Th1-like) in both the mesenteric lymph nodes and the spleen 4 days after immunization. The failure of KLH to expand the CD45RC+CD4+ subset could be due to the stress-induced reduction in IFN-gamma levels reported in cells taken at the time of immunization. Implications of these findings as a mechanism for the decrease in the in vivo antibody response previously reported is discussed.

Animals↗
PubMed1995

Peripheral catecholamines are involved in the neuroendocrine and immune effects of LPS.

There is evidence for bidirectional communication between the brain and the immune system. The immune system is subjected to neuroendocrine influences and reciprocally the hypothalamopituitary-adrenal axis is modulated by immune signals. Lipopolysaccharides (LPS), used to mimic infectious/inflammatory diseases, induce a series of stress markers, including modifications of monoaminergic transmission, enhancement of HPA axis activity, and decreased immune activity. In the present work we investigated the participation of peripheral catecholamines in the immune and endocrine responses to LPS in vivo. We studied the effects of LPS after chemical sympathectomy using 6-hydroxydopamine (6-OHDA), which does not cross the brain-blood barrier (BBB) in adults when peripherally injected. 6-OHDA administration was able to interfere with the effects of LPS on immune cells; however, the effects depended on the lymphoid tissue tested. In fact, the depression of mitogenesis induced by LPS was reversed by 6-OHDA in the spleen but not in the thymus. Moreover, 6-OHDA also interfered with the endocrine modifications induced by LPS. This neurotoxin completely or partially inhibited the effect of LPS on ACTH and corticosterone secretion, respectively. Taken together, these results clearly demonstrate that in vivo, the peripheral sympathetic nervous system participates in the immune and endocrine effects of LPS.

Adrenocorticotropic Hormone↗
PubMed1995

Regulation of the HPA axis by cytokines.

Cytokines are a group of polypeptide mediators, classically associated with the regulation of immunity and inflammation. However, these peptides regulate not only local immune/inflammatory responses, but also elicit many CNS-mediated responses which accompany such immune/inflammatory reactions. This article reviews the evidence that interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNFalpha) produce hypothalamo-pituitary-adrenal (HPA) axis activation in response to various threats to homeostasis. To aid such an examination, and to gain insights into the potential mechanisms by which these cytokines influence the HPA axis, experimental findings are discussed within a framework of criteria. If a particular cytokine plays a significant role in the regulation of the HPA axis in response to a particular pathophysiology, then necessarily: (1) receptors for that cytokine should be present within tissues associated with the HPA axis; (2) administration of that cytokine should elicit HPA activation; (3) the HPA axis should be exposed to that cytokine; and (4) inhibition of the action of that cytokine should prevent HPA activation. The evidence discussed indicates that some, if not all, of these criteria are met for each of IL-1, IL-6, and TNFalpha. However, the extensive interactions between different cytokines, the broad spectrum of pathophysiologies associated with increased cytokine production (including inflammatory and non-inflammatory stresses), and the number of tissues/cells capable of either synthesizing or responding to cytokines, suggest that multiple mechanisms mediate the influence of cytokines on the HPA axis.

Animals↗
PubMed1995

Modulation of interleukin-1 receptors in the brain-endocrine-immune axis by stress and infection.

We summarize data from some of our recent studies on in vitro and in vivo modulation of interleukin-1 (IL-1) receptors in the mouse brain-endocrine-immune axis by stress and infection. Ether-laparotomy stress in mice resulted in a selective increase in pituitary IL-1 receptors and a significant decrease in pituitary receptors for corticotropin-releasing factor (CRF), a major regulator of the endocrine response to stress. Intraperitoneal injection of rat/human CRF mimicked the effects of stress and resulted in a dramatic increase in [125I]IL-1alpha binding in the pituitary; [125I]IL-1alpha binding in the hippocampus, spleen, and testis was unaffected by stress or CRF treatment. Glucocorticoid treatment with dexamethasone alone did not alter [125I]IL-1alpha binding but significantly inhibited CRF-induced upregulation of IL-1 receptors in the pituitary. The intracellular mechanism(s) involved in stress and CRF-induced upregulation of IL-1 receptors in the pituitary gland were examined by evaluating the effects of treatment of AtT-20 mouse pituitary corticotroph cells with a variety of neuroendocrine mediators of stress. CRF, forskolin, and isoproterenol (beta2 adrenergic receptor agonist) produced dose-dependent increases in cAMP production and [125I]IL-1alpha binding. In contrast, somatostatin and dexamethasone significantly inhibited CRF-stimulated increase of cAMP production and [125I]IL-1alpha binding, suggesting a primary role for cAMP in the regulation of pituitary IL-1 receptors. Next, we investigated the modulation of IL-1beta levels and IL-1 receptors following infection of mice with the endotoxin, lipopolysaccharide (LPS). Acute administration of low doses of endotoxin (30 mu g LPS/mouse) dramatically increased IL-1beta levels and reciprocally decreased [125I]IL-1alpha binding in peripheral tissues (pituitary, testis, liver, and spleen) but not in brain (hippocampus). This effect appeared to be dose related since higher doses of endotoxin (300 mu g LPS/mouse) significantly decreased [125I]IL-1alpha binding in both peripheral tissues and brain. Endotoxin induced modulation of the IL-1 system was also dependent on the treatment regimen since two low-dose LPS injections (at 0 and 12 h) increased IL-1beta concentrations and decreased [125I]IL-1alpha binding in both central and peripheral tissues. These data provide further support for a role for IL-1 in coordinating brain-endocrine-immune responses to stress and infection.

Anesthetics, Inhalation↗
PubMed1995

Stress downregulates lipopolysaccharide-induced expression of proinflammatory cytokines in the spleen, pituitary, and brain of mice.

Mice injected with LPS (10 mu g/mouse, sc) or saline were submitted to a 15-min restraint stress and sacrificed 1 or 2 h later to assess the effect of stress on the induction of interleukin-1beta (IL-1beta) and other proinflammatory cytokines (IL-1alpha, IL-1ra, IL-6, and tumor necrosis factor-alpha) in the spleen, pituitary, hypothalamus, hippocampus, and striatum. LPS-induced cytokine gene expression, as determined by comparative RT-PCR, was lower in stressed than in nonstressed mice. LPS increased plasma and tissue levels of IL-1beta, as determined by ELISA, but this effect was less marked in stressed than in nonstressed mice. These results are discussed in relation to the modulatory effects of glucocorticoids on cytokine production.

Animals↗
PubMed1996

Insular cortex lesions impair the acquisition of conditioned immunosuppression.

Conditioned immunosuppression can be readily obtained in animals by associating a taste with an immunosuppressive drug. On subsequent exposure to the conditioned taste, the animals show an attenuated immune response and also exhibit a conditioned taste aversion. It has been established that insular cortex lesions disrupt the acquisition of conditioned taste aversion. The effect of NMDA-induced lesions in either the insular cortex or the parietal cortex of male Wistar rats was evaluated in the acquisition of conditioned immunosuppression in two experiments. Unlesioned control rats showed the conditioned immunosuppressive response after reexposure to the taste, as indicated by lower hemagglutinating titers to sheep red blood cells in the first experiment and by a decreased IgM production to ovalbumin, measured by ELISA, in the second experiment. Insular cortex-lesioned rats did not show the conditioned immunosuppression in either experiment, while parietal cortex lesions and the sham-lesioned animals presented a clear decrease of hemagglutinating titer and a low IgM production. The insular cortex lesions did not affect the normal immune response, showing normal hemagglutinating titers and IgM production when compared to nonconditioned controls. The immunosuppressive action of cyclophosphamide also remained unaltered. In conclusion, these results show that the insular cortex is essential for the acquisition of conditioned immunosuppression.

Animals↗
PubMed1997

Involvement of central neurotensin in thermoregulatory and neuroimmune function in pregnant rats exposed to heat.

To examine a functional relationship among pregnancy and central neurotensin and thermoregulatory and neuroimmune systems during heat stress, we monitored colonic temperature in six virgin female rats and six pregnant rats (9 to 11 days gestation) exposed to a microwave source. We also assayed splenic natural killer cell activity (NKCA), blood corticosterone (CS), and ACTH as indicators of the hypothalamic-pituitary-adrenal axis, beta-endorphin (beta-EP), and neurotensin (NT) in discrete brain regions. Additionally, we clarified the effects of intracerebroventricular (icv) administration of NT antiserum on these same responses in pregnant rats exposed to heat stress. Repeated-measures analysis of variance showed significant main effects of heat and pregnancy and a significant interactive effect on colonic temperature. Significant elevation in blood CS, ACTH, beta-EP, and NT in the hypothalamus and significant reductions in splenic NKCA and NT in the nucleus accumbens were produced by heat. In the experiment examining the effect of icv administration of NT antiserum, significant main effects of heat and administration and a significant interactive effect on colonic temperature were observed. Icv administration of NT antiserum increased splenic NKCA and decreased blood beta-EP. These results show that pregnancy enhances thermal homeostasis, suggesting central thermoregulatory mechanisms through NT in nucleus accumbens and hypothalamus in which placental or pituitary beta-EP may be involved. NT and beta-EP seem to play central roles simultaneously in heat-induced immunosuppression during pregnancy. Clarification for the effects of NT antiserum on beta-EP in virgin rats or manipulation of agents related to opioid system should be the focus of future work.

Adrenocorticotropic Hormone↗
PubMed1998

Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning.

The reported experiments explore the effects of peripheral LPS administration on learning and memory processes. As measured by the conditioned freezing response, intraperitoneal LPS administration given after conditioning impaired contextual but not auditory-cue fear conditioning in both juvenile (hooded Long Evans) and adult rats (albino Sprague Dawley) of two different strains. This impairment in contextual fear conditioning was not dependent on the presence of the tone. Preexposure to the context eliminated the effect of LPS on contextual fear conditioning, and in addition, LPS given after context preexposure negated the beneficial effects of preexposure on contextual fear. These results suggest that LPS disrupts posttrial memory consolidation processes. In support of the hypothesis that LPS-induced proinflammatory cytokine release is involved in producing the impairment in contextual fear caused by LPS, peripheral interleukin-1 receptor antagonist (IL-1ra) administered subcutaneously at a dose of 100 mg/kg prevented the impairment in contextual fear caused by LPS. These experiments provide evidence for a role of immune activation and cytokine activity in learning and memory processes.

Acoustic Stimulation↗