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D J Carr

Publications and source records attributed to D J Carr.

At least 73 records · Page 4Linked to original sources
PubMed1994

Naltrexone antagonizes the analgesic and immunosuppressive effects of morphine in mice.

A study was undertaken to investigate the relationship between morphine-induced analgesia and immunosuppression after acute administration. In male CD1 mice, morphine (10.0-100.0 mg/kg s.c.) produced a U-shaped immunosuppressive dose-effect curve on splenic natural killer (NK) activity. Morphine also induced dose-related analgesia, as measured by an increase in tail-flick latency during thermal application; these analgesic effects were antagonized by naltrexone (1.0-10.0 mg/kg). In addition, morphine-induced suppression of splenic NK activity was antagonized in a dose-dependent manner and, at one dose of naltrexone (10.0 mg/kg), splenic NK activity was augmented. To investigate further the relationship between naltrexone antagonism of morphine-induced analgesia and immunomodulation, single doses of morphine (10.0-100.0 mg/kg) were administered to mice pretreated with naltrexone (0.01-10.0 mg/kg) or saline. A dose of 10.0 mg/kg of morphine produced 35% of the maximal possible effect in the analgesia study and no immunosuppression, whereas a dose of 32.0 mg/kg produced a maximal analgesic effect and significant suppression of NK activity. Naltrexone blocked morphine-induced analgesia and immunosuppression in a dose-dependent fashion. Moreover, the combination of 1.0 mg/kg of naltrexone and 32.0 mg/kg of morphine elevated splenic NK activity. A large dose of morphine (100.0 mg/kg) elicited full analgesia and had no effect on splenic NK activity in saline- or naltrexone-pretreated mice. Collectively, these results support the view that, in mice, morphine-induced analgesia and immunosuppression are mediated through a common opioid receptor type.

Animals↗
PubMed1993

Characterization of a (+)-azidophenazocine-sensitive sigma receptor on splenic lymphocytes.

A study was undertaken to structurally define and functionally assess sigma receptors on splenocytes using the highly selective sigma ligand (+)-azidophenazocine. Radioreceptor assays under reduced lighting show (+)-azidophenazocine can effectively block the binding of sigma ligands [3H]haloperidol (IC50 = 30 nM, Ki = 19.0 nM) and [3H](+)-pentazocine (IC50 = 40 nM, Ki = 350 nM), but not the dopamine (D2) ligand [3H]spiperone (IC50 > 5 microM) to splenic lymphocytes. [3H](+)-1-Propyl-3-(3-hydroxyphenyl)piperidine ([3H](+)-PPP) sites (Kd = 40.8 nM, Bmax = 2.32 pmol/mg) were also present on these lymphocytes. Additional studies using [3H](+)-azidophenazocine indicated the presence of saturable sites (Kd = 29.7 nM, Bmax = 760 fmol/mg) on splenic lymphocytes. There are no significant differences in affinity between sites found on T-enriched (Kd = 59 +/- 47 nM) and B-enriched lymphocytes (Kd = 23 +/- 5 nM). Photoaffinity labeling studies of splenocyte membranes with [3H](+)-azidophenazocine revealed a protein migrating at an apparent m.w. of 57 kDa under reducing and nonreducing conditions on SDS-PAGE. The labeling was specific because pretreatment with unlabeled haloperidol, (+)-PPP, 1,3 di(2-tolyl)guanidine, (+)-pentazocine, and (+)-azidophenazocine before cross-linking competed away > 75% of the radioactivity associated with the protein, whereas (-)-pentazocine and naloxone were significantly less effective. This data together with the observation that both (+)-azidophenazocine or haloperidol inhibit Con A-induced production of IFN by splenocytes, indicates that lymphocytes possess a biologically relevant sigma receptor.

Affinity Labels↗
PubMed1993

Immune alterations in chronic morphine-treated rhesus monkeys.

Both immune and neuroendocrine abnormalities have been documented in heroin abusers. We investigated immunocompetence of peripheral blood mononuclear cells (PBMs) among separate groups of rhesus monkeys that were drug naive or received morphine either infrequently (twice/week) or daily (3.2 mg/kg). Both infrequent and daily morphine-exposed monkeys showed a decrease (10%) in the percentage of CD4+ circulating lymphocytes and an increase (19%) in the percentage of CD8+ cells. However, monkeys exposed daily to morphine showed a 30% increase in the helper-inducer CD4+ lymphocytes, CD4+CD29+, compared to untreated controls. PBMs taken from animals exposed daily to morphine responded poorly to forskolin in the production of cAMP compared with cells obtained from untreated animals. However, cells from monkeys that received morphine infrequently had elevated levels of cAMP in response to forskolin. These results suggest relatively low doses of morphine have a significant effect on immunocompetence in rhesus monkeys which parallels the effects observed in the opioid-dependent human population. Therefore, rhesus monkeys will provide a beneficial animal model to study the effects of opioid compounds on immunocompetence during exposure, withdrawal and substitution drug therapy in opioid-dependent animals.

Animals↗
PubMed1993

Immune alterations in morphine-treated rhesus monkeys.

The effect of morphine treatment on immunocompetence was investigated in rhesus monkeys (Mucaca mulatta). Monkeys that received morphine daily (3.2 mg/kg) had suppressed peripheral blood mononuclear cell (PBMC) natural killer (NK) activity as well as a decrease in the percentage of CD8+CD16+ cells compared with saline-treated (controls) or infrequently treated (i.e., opioids once or twice weekly) monkeys. However, an increase (20 +/- 5%) in the percentage of CD8+ lymphocytes was found in both the daily and infrequent opioid-treated monkeys compared with controls. Conversely, the percentage of total CD4+ lymphocytes and CD4+CD45RA+ was reduced (12 +/- 2% and 28 +/- 10% respectively) in both daily and infrequent opioid-treated animals compared with saline-treated controls. In a reciprocal fashion, there was an increase in the CD4+CD29+ population in daily morphine-treated monkeys (54% of the total CD4+ cells) compared with untreated animals (37% of the total CD4+ cells). In addition, cultured PBMC obtained from monkeys treated daily with morphine produced significantly (P < .01) more polyclonal immunoglobulin (Ig) G (366 ng/ml) and polyclonal IgM (233 ng/ml) compared with PBMC production of polyclonal IgG (96 ng/ml) and polyclonal IgM (67 ng/ml) from saline-treated controls. However, no differences were found in the percentage of CD19+ lymphocytes among any of the groups. In summary, daily treatment with a relatively low dose of morphine (3.2 mg/kg) affects immunocompetence which could have important implications in the regulation of viral pathogens in i.v. drug abusers (e.g., AIDS).

Animals↗
PubMed1993

Alpha adrenergic and mu-2 opioid receptors are involved in morphine-induced suppression of splenocyte natural killer activity.

The immunosuppressive effects following acute morphine administration have been mapped to opioid receptors in the central nervous system, specifically to the periaqueductal gray matter of the mesencephalon. The mesencephalon is associated with sympathetic neuronal processes, and the spleen is innervated with sympathetic neurons that are in direct apposition with lymphocytes in the periarteriolar lymphatic sheath. Accordingly, we investigated adrenergic involvement following morphine administration on natural killer (NK) activity by splenic lymphocytes. Acute morphine administration (25 mg/kg s.c.) suppresses (30-50%) NK activity by murine splenic immunocytes as measured in a 4-hr 51Cr-release assay. The suppression is blocked by phentolamine (4 mg/kg) and propranolol (10 mg/kg) in a dose-dependent fashion. However, phentolamine (2 mg/kg), but not propranolol (5 mg/kg), can also effectively antagonize morphine-induced immunosuppression. In addition, phentolamine (4 mg/kg) and prazocin (1 mg/kg), but not yohimbine (1 mg/kg), antagonizes morphine-elicited suppression of splenic NK activity. Selective opioid receptor antagonists were also utilized to determine the type or subtype of receptor activated following morphine administration. beta-Funaltrexamine (40 mg/kg) but not naloxonazine (35 mg/kg), naltrindole (20 mg/kg) or norbinaltorphimine (10 mg/kg) effectively blocks morphine-induced suppression of splenic NK activity. Collectively, morphine interacts with 1) mu-2 opioid receptors (most probably centrally) and 2) activates both alpha and beta adrenergic pathways.

Animals↗
PubMed1992

Phentolamine but not propranolol blocks the immunopotentiating effect of cold stress on antigen-specific IgM production in mice orally immunized with sheep red blood cells.

The effect of cold stress on immunocompetence was investigated in mice intragastrically intubated with sheep red blood cells. Cold stress was found to consistently augment total IgG and IgM production by splenic lymphocytes. In addition, antigen-specific IgM production by cultured splenic lymphocytes obtained from cold stressed animals was enhanced compared to unstressed mice. However, serum levels of total and antigen-specific immunoglobulins were suppressed or unaltered following cold stress. The alpha-adrenoceptor antagonist, phentolamine, could block the effects mediated by cold stress while the beta-adrenoceptor antagonist, propranolol, potentiated the action of cold stress. Taken together, the data indicate cold stress-mediated enhancement in immunoglobulin production by orally immunized animals takes place through the activation of alpha-adrenergic pathways. The results also suggest alpha- and beta-adrenergic pathways independently regulate antibody production following oral administration of antigen. These observations illustrate the integrative nature of the immune and neuroendocrine systems.

Animals↗
PubMed1992

Neuroendocrine peptide receptors on cells of the immune system.

The functional role of neuropeptide receptors in the immune system seems to be sensory and regulatory. Signaling molecules (i.e. neuropeptides/neurotransmitters) secreted by immune or neuroendocrine cells can interact with specificity to immunocyte membrane bound neuroendocrine peptide receptors resulting in changes in immune homeostasis. At the onset of this review, three criteria were established in order to formally define the existence of a receptor including the pharmacologic, biochemical, and biological profiles. Applying these criteria, at least ten neuroendocrine peptide/peptide neurotransmitter receptors have met the requirements (table 1). Perhaps more striking, many of these receptors have characteristics which are nearly identical to those receptors found on neuroendocrine tissue. This observation implies irregularities in the physiology of a receptor system in one tissue compartment (neuroendocrine or immune) may be mirrored by the receptors found in the other compartment (neuroendocrine or immune) as well. This rather hypothetical concept is, in fact, supported by data studying ACTH, CRH, and TRH receptors on immune cells relative to the expression or function of these receptors in neuroendocrine tissue taken from patients with neuroendocrine disorders. It is likely that future work will use this relationship to further study the dynamic interaction between the immune and neuroendocrine systems in defining neurologic, neuroendocrine, and autoimmune disorders.

Animals↗
PubMed1992

Phosphatidylserine suppresses antigen-specific IgM production by mice orally administered sheep red blood cells.

Phosphatidylserine is an endogenous acidic phospholipid that has been shown to modulate nervous system function. In the immune system, phosphatidylserine has been shown to suppress T dependent and T independent immune responses after systemic administration of antigen and lipid. However, no studies on the possible regulation by phosphatidylserine on mucosal immunity have been undertaken. Therefore, we studied the action of phosphatidylserine on immunocompetence using orally immunized mice. Mice orally administered phosphatidylserine (25 mg/kg/day) and subsequently intubated intragastrically with sheep red blood cells showed a significant decrease in antigen-specific IgM production by splenic lymphocytes compared with controls. Furthermore, the response of splenic lymphocytes obtained from phosphatidylserine-treated, antigen-primed animals to antigen or pokeweed mitogen in proliferation assays was markedly suppressed, compared with splenic lymphocytes obtained from nontreated, antigen-primed mice. Similarly, splenic lymphocytes from phosphatidylserine-treated, antigen-primed animals cultured in the presence of antigen produced no measurable interleukin 4 and low levels of interleukin 2, whereas splenic lymphocytes from antigen-primed animals produced measurable levels of interleukin 4 and significantly higher levels of interleukin 2. By fluorescence-activated cell sorter analysis, brightly stained B lymphocytes (Ig+) take up a larger portion of phosphatidylserine than do brightly stained T lymphocytes (Thy 1.2+). Collectively, these results point to the immunosuppressive qualities of phosphatidylserine. Given that phosphatidylserine is released upon injury and destruction of eukaryotic cells, these results suggest that phosphatidylserine may be an endogenous anti-inflammatory molecule.

Animals↗
PubMed1992

Immunoregulatory properties of (+)-pentazocine and sigma ligands.

(+)-Pentazocine, phencyclidine, and other sigma ligands including 1,3-di-(o)-tolylguanidine (DTG), (+)-1-propyl-3-(3-hydroxyphenyl) piperidine [(+)-PPP] and haloperidol were investigated for their potential immunoregulatory properties. High concentrations (10(-5) M) of DTG and haloperidol were found to suppress in vitro murine splenocyte natural killer activity while equivalent concentrations of (+)-pentazocine, (-)-pentazocine and (+)-PPP were without effect. In a reciprocal fashion, lower doses (10(-9) M) of DTG enhanced natural killer activity. Sigma ligands were also found to affect in vitro polyclonal immunoglobulin production following mitogen stimulation. Specifically, high concentrations (10(-6) M) of haloperidol significantly (P < 0.001) suppressed pokeweed mitogen (PWM)-stimulated IgG and IgM production, yet enhanced lipopolysaccharide (LPS)-stimulated IgM production by murine splenocytes. Lower concentrations (10(-8) to 10(-10) M) enhanced (two- to fourfold) PWM-induced IgM production and LPS-stimulated IgG and IgM production. At high concentrations (10(-6)), (+)-pentazocine suppressed (P < 0.01) LPS-induced polyclonal IgG and IgM but enhanced (P < 0.01) PWM-induced IgM production. Both DTG and (-)-pentazocine (10(-8) to 10(-10) M) significantly augmented (two- to threefold) LPS-stimulated murine splenocyte production of polyclonal IgM. Intracellularly, (-)-pentazocine (10(-9) M), haloperidol (10(-7) M), DTG (10(-7) M) and (+)-PPP (10(-5) to 10(-9) M) enhanced forskolin (10(-6) M)-induced cAMP production in splenic lymphocytes while (+)-pentazocine was without effect. Collectively, the data suggest functional and biologically relevant sigma receptors on cells of the immune system.

Animals↗
PubMed1992

Clinical effects of a sorbent suspension dialysis system in treatment of hepatic coma (the BioLogic-DT).

Fifteen patients with acute deterioration of liver function, high serum ammonium, and an average coma level of 3.9 were identified. Eleven of the patients were on respirator support, and eleven had kidney failure pursuant to the liver failure. The patients were treated for 8-12 hours daily with the BioLogic-DT system, in which membranes of a cellulosic plate dialyzer actively pump blood through a single access at over 200 ml/min, and the dialysate contains a suspension of powdered activated charcoal (300,000 square meters surface area) and cation exchanger (160 meq capacity). No anticoagulant was used. In spite of the declining condition of the patients prior to treatment, there was a statistically significant improvement in neurologic status during individual treatments, and a positive trend over 1-12 (average four) daily treatments. Four patients recovered liver function and another four improved enough to receive a liver transplant operation. The BioLogic-DT system appears to be safe in treatment of patients with hepatic insufficiency and coma. The neurologic improvement of these patients indicates that many toxins of hepatic failure are dialyzable across cellulosic membranes and bound by charcoal.

Acute Disease↗
PubMed1992

Evaluation of conventional and radiometric fecal culture and a commercial DNA probe for diagnosis of Mycobacterium paratuberculosis infections in cattle.

Radiometric (RCM) and conventional fecal culture (HEY) and a commercial polymerase chain reaction/DNA probe were evaluated as diagnostic tests for subclinical paratuberculosis in dairy cattle using fecal specimens from a repository of paratuberculosis specimens. The case definition of subclinical bovine paratuberculosis was isolation of Mycobacterium paratuberculosis, by conventional or radiometric culture, from fecal samples or internal organs of dairy cattle without diarrhea or chronic weight loss. Animals designated as free of the disease originated exclusively from certified paratuberculosis-free herds in Wisconsin. Among 182 infected cattle, RCM and HEY fecal culture and the DNA probe had test sensitivities of 54.4%, 45.1% and 33.5%, respectively. Fecal samples from only 111 of the M. paratuberculosis-infected cows tested positive by at least one of the three tests and these cows were designated as fecal shedders; the remaining 71 were considered to have prepatent infections. Among the 111 M. paratuberculosis fecal shedders, RCM, HEY and the probe detected the organism in 89.2%, 73.8% and 55.0% of the fecal specimens, respectively. Herd prevalence significantly affected the sensitivity of all three diagnostic tests (p less than 0.05) but only affected the fecal shedder detection efficiency of the DNA probe (p less than 0.01). No positive DNA probe results were found on 100 randomly selected fecal samples from cows in four certified paratuberculosis-free herds, thus the DNA probe was 100% specific. Probe analyses could be performed in 24 h or less. Time to complete the culture-based tests was 12 wk for HEY and 7 wk for RCM.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Enantioselective kappa opioid binding sites on the macrophage cell line, P388d1.

A kappa (kappa) opioid binding site has been characterized on the macrophage cell line, P388d1, using the kappa selective affinity ligand, [3H] (1S,2S)-(-)-trans-2-isothiocyanato-N-methyl-N-[2-(1- pyrrolidinyl) cyclohexyl] benzeneacetamide (-)BD166). The kappa site has a relative molecular mass (Mr) of 38,000 under nonreducing conditions and 42,000 under reducing conditions. Moreover, it exhibits enantioselectivity in that 1S,2S-(-)-trans-3,4-dichloro-N-methyl-N-[2-1-pyrrolidinyl)cyclohexyl] benzeneacetamide ((-)-U-50,488) blocks [3H](5 alpha, 7 alpha, 8 beta)-(-)-N-methyl-N-[7-(1- pyrrolidinyl)-1-oxaspiro-(4,5)-dec-8-yl]benzeneacetamide (U-69,593) binding to P388d1 cells with an IC50 = 7.0 nM whereas 1R,2R-(+)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide ((+)U-50,488) blocks [3H]U-69,593 binding to P388d1 cells with an IC50 = 7000 nM.

Autoradiography↗
PubMed1991

Functional assessment and partial characterization of [3H](+)-pentazocine binding sites on cells of the immune system.

The existence of sigma receptors on lymphocytes and thymocytes was characterized using [3H](+)-pentazocine. [3H](+)-Pentazocine specifically labels high affinity sigma-type binding sites on T- and B-enriched lymphocyte membranes. The binding is saturable with T lymphocyte sites having a KD value of 401 +/- 85 nM and B lymphocyte sites having a KD value of 302 +/- 46 nM. Likewise, saturable high (KD1 277 +/- 92 nM) and low (KD2 2.5 +/- 1.2 microM) affinity sites for [3H](+)-pentazocine are found on thymocytes as well. In competition studies with lymphocytes, the rank order of potency for competing ligands is (+)-pentazocine = N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2- (1-pyrrolidinyl)ethylamine (BD1008) greater than 1R,2S-(+)-cis-N-(2-(3,4-dichlorophenyl)ethyl]-2- (1-pyrrolidinyl)cyclohexylamine (LR132) greater than or equal to (-)-pentazocine greater than or equal to phenazocine greater than (+/-)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide methanesulphonate (U-50,488H) = phencyclidine greater than haloperidol = 1,3-di- (o)-tolylguanidine. In competition studies with thymocytes, the rank order of potency for competing ligands is (+)-pentazocine = BD1008 greater than or equal to phenazocine greater than haloperidol greater than 1,3-di-(o)-tolylguanidine greater than phencyclidine greater than (-)-pentazocine. These compounds were also investigated as potential regulatory molecules in mitogen-stimulated lymphocyte proliferation assays. Of the compounds tested, phencyclidine, 1,3-di-(o)-tolylguanidine, haloperidol, and (+)-pentazocine suppress concanavalin A-induced proliferation at high (10(-5) M) concentrations while (-)-pentazocine is inactive. When pokeweed mitogen or lipopolysaccharide are used, these compounds enhance or suppress lymphocyte proliferation depending on the mitogen and concentration of ligand. These results indicate a stereoselective receptor for (+)-pentazocine which is coupled to biological processes of lymphocytes.

Animals↗
PubMed1991

Naloxone administration in vivo stereoselectively alters antigen-dependent and antigen-independent immune responses.

An investigation was conducted to determine the role naloxone has on immunocompetence in vivo. Mice (n = 7) injected with sheep red blood cells and treated with naloxone (0.1-10.0 mg/kg) show an enhanced production of total and antigen-specific IgM antibody by splenic lymphocytes compared to control (mock-treated) mice. The response was dose-dependent, with the greatest effect occurring at 0.1 mg/kg naloxone. A naloxone dose of 0.001 mg/kg was not active. In addition, natural killer activity was enhanced in the naloxone-treated mice compared to the controls. The effects on antigen-specific antibody production and natural killer activity were stereoselective, since (-)-naloxone is active whereas (+)-naloxone was not. These results illustrate the ability of an opioid receptor antagonist administered in vivo to regulate immunocompetence to antigen-specific and antigen-nonspecific immune responses, which may be useful during selective inflammatory processes.

Animals↗
PubMed1991

The role of endogenous opioids and their receptors in the immune system.

Opioid peptides appear to be dynamic signaling molecules that are produced within the immune system and are active regulators of an immune response. Furthermore, the receptors for these peptides occurring on immunocyte membranes share characteristics with neuronal opioid receptors, including molecular size, immunogenicity, and the use of specific intracellular signaling pathways. Recent studies of the interaction of opioids with cytokines have indicated that opioid peptides are intimately involved within the immune system. Specifically, opioids, including 2-n-pentyloxy-2-phenyl-4-methyl-morpholine, naloxone, and beta-endorphin, have been shown to interact with IL-2 receptors (134) and regulate production of IL-1 and IL-2 (48-50, 135). Conversely, IL-1 has been shown to up-regulate opioid peptide binding in brain tissue (136). Furthermore, the induction of IL-1 by opioids has also been identified in the invertebrate Mytilus, indicating the evolutionary conservation of this relationship (137). These results seem to typify the intricate association between the immune and neuroendocrine systems through opioid pathways. It is predicted that future endeavors will use this relationship to diagnose and treat specific diseases that have at their basis neuroendocrine and immunologic imbalances.

Animals↗
PubMed1990

Differential effect of opioids on immunoglobulin production by lymphocytes isolated from Peyer's patches and spleen.

The mucosal immune system plays an important role in blocking the penetration of invasive organisms into various mucosal surfaces. Evidence now suggests neuroendocrine peptide hormones have immunomodulatory properties, including the ability to alter mucosal immunity. The potential for opioid compounds and corticotropic hormone (ACTH) to modulate mucosal immune function was investigated. We have found beta-endorphin, ACTH, and naltrindole (delta-class opioid receptor antagonist) to significantly suppress concanavalin A-stimulated Peyer's patch lymphocyte immunoglobulin production of IgA, IgG, and IgM isotypes. Oxymorphindole, a delta class opioid receptor agonist, significantly decreased IgM but not IgA or IgG production by the mitogen-stimulated Peyer's patch lymphocytes. Both oxymorphindole and naltrindole modestly reduced interleukin-2 receptor expression of concanavalin A- (Con A)-stimulated splenic and Peyer's patch lymphocytes. Neither compound appreciably affected immunoglobulin production by lipopolysaccharide-stimulated Peyer's patch lymphocytes. Collectively, these results indicate stress-related peptides such as ACTH and opioids may be involved in the regulation of immunoglobulin synthesis by Peyer's patch lymphocytes.

Adrenocorticotropic Hormone↗