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Biomedical subjects

R J Weber

Publications and source records attributed to R J Weber.

At least 19 recordsLinked to original sources
PubMed1999

Suppression of splenic macrophage functions following acute morphine action in the rat mesencephalon periaqueductal gray.

Morphine action in the periaqueductal gray (PAG) matter of the mesencephalon suppresses T cell proliferation and NK cell activity through actions at mu opioid receptors. We investigated the effect of acute microinjection of morphine in the rat PAG on macrophage function. We found that morphine injection in the PAG significantly (p <.01) suppressed nitric oxide production by untreated (82 +/- 23% suppression), IFN-gamma-primed (57 +/- 11% suppression), and LPS-activated (50 +/- 7% suppression) splenic macrophages and did not alter macrophage viability. In contrast, IFN-gamma- and LPS-activated macrophages from PAG-injected saline rats generated an increased output of nitric oxide, which was associated with significant (p <.01) reduction in cell viability. Morphine significantly (p <.01) inhibited TNF-alpha production by LPS-activated macrophages (28 +/- 8% inhibition compared with PAG-injected saline rats). In addition, morphine significantly (p <. 05) inhibited phagocytosis of Candida albicans by resident macrophages (40 +/- 20% inhibition compared with that of macrophages from PAG-injected saline rats). Responses of resident or activated macrophages from PAG-injected saline and untreated control groups did not differ significantly. The results of this ex vivo study suggest that suppressive effects of morphine on macrophage functions may contribute to increased susceptibility to infectious diseases and cancer associated with drug abuse.

Analgesics, Opioid↗
PubMed1999

Inhibition of interleukin-2 production and downregulation of IL-2 and transferrin receptors on rat splenic lymphocytes following PAG morphine administration: a role in natural killer and T cell suppression.

We investigated the effects of acute injection of morphine into the rat mesencephalon periaqueductal gray (PAG), on splenic natural killer (NK) cell and lymphocyte functions, interleukin-2 (IL-2) production, expression of T cell (CD3), T helper cell (CD4), T suppressor cell (CD8), and NK cell (NKR-P1) surface markers, and expression of IL-2 (CD25) and transferrin (CD71) receptors. Bilateral microinjection of 10 nmol of morphine in the PAG significantly (p < 0.001) inhibited IL-2 (31%) production by activated splenic lymphocytes compared with that of PAG saline-injected control rats. In addition, morphine significantly (p < 0.01) suppressed splenic NK cell activity (14-33%) and T lymphocyte proliferative responses (25-48%) to various mitogens compared with controls. Furthermore, morphine did not alter the expression of CD3, CD4, CD8, and NKR-P1 surface markers, but significantly (p < 0.001) downregulated the expression of CD25 and CD71 receptors following in vitro activation. These results suggested that injection of morphine in the PAG suppresses NK and T cell functions by reducing the ability of T cells to produce IL-2 and downregulating the expression of CD25 and CD71 surface activation markers.

Animals↗
PubMed1999

Polarity of the mouse embryo is anticipated before implantation.

In most species, the polarity of an embryo underlies the future body plan and is determined from that of the zygote. However, mammals are thought to be an exception to this; in the mouse, polarity is generally thought to develop significantly later, only after implantation. It has not been possible, however, to relate the polarity of the preimplantation mouse embryo to that of the later conceptus due to the lack of markers that endure long enough to follow lineages through implantation. To test whether early developmental events could provide cues that predict the axes of the postimplantation embryo, we have used the strategy of injecting mRNA encoding an enduring marker to trace the progeny of inner cell mass cells into the postimplantation visceral endoderm. This tissue, although it has an extraembryonic fate, plays a role in axis determination in adjacent embryonic tissue. We found that visceral endoderm cells that originated near the polar body (a marker of the blastocyst axis of symmetry) generally became distal as the egg cylinder formed, while those that originated opposite the polar body tended to become proximal. It follows that, in normal development, bilateral symmetry of the mouse blastocyst anticipates the polarity of the later conceptus. Moreover, our results show that transformation of the blastocyst axis of symmetry into the axes of the postimplantation conceptus involves asymmetric visceral endoderm cell movement. Therefore, even if the definitive axes of the mouse embryo become irreversibly established only after implantation, this polarity can be traced back to events before implantation.

Animals↗
PubMed1998

Opioid mediated effects on the immune system: sympathetic nervous system involvement.

Opioids have been hypothesized to suppress parameters of immune function by acting within the central nervous system to increase the activity of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Production of catecholamines and adrenocorticoids have been demonstrated to be responsible for many of the observed immunomodulatory effects which occur following opioid administration. In general, the sympathetic nervous system has been shown to play a role in regulating lymphocyte proliferation and natural killer cell activity as well as several other parameters of immune function. Here, we will focus primarily on the role of the sympathetic nervous system in modulating opioid induced immunosuppression. The role of the hypothalamic-pituitary adrenal axis is reviewed elsewhere in this issue.

Animals↗
PubMed1998

Centrally-mediated opioid-induced immunosuppression. Elucidation of sympathetic nervous system involvement.

Opioid-induced modulation of the immune system is a complex phenomenon involving opioid receptors, central and sympathetic neural pathways, catecholamine receptors, and other regulatory mechanisms. The precise neural pathways involved in centrally-mediated immune modulation are not currently defined. In addition, the physiological purpose for endogenous opioid modulation of the immune system is not well understood. Perhaps this modulation phenomenon represents an integral feedback loop within a much larger homeostatic control system. Indeed, the role of the HPA axis in immune regulation can not be discarded, and in fact, probably serves to balance immune function, in concert with multiple feedback systems, around some undiscovered parameter of efficiency. Perhaps the physiological role of endogenous opioid control is to act as a monitor poised to subvert chronic inflammatory processes and autoimmune disorders. Regardless of the evolutionary heritage of this and despite the overwhelming complexity of immune regulation, important work substantiating a bidirectional communication link between the brain and the immune system has created a foundation for further elucidation of the intricacies of immunoregulation.

Animals↗
PubMed1998

Rat natural killer cell, T cell and macrophage functions after intracerebroventricular injection of SNC 80.

We investigated the effects of (+)-4-[(alpha R)-alpha-((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide (SNC 80), a nonpeptidic delta-opioid receptor-selective agonist, on rat leukocyte functions. Intracerebroventricular injection of SNC 80 (20 nmol) in Fischer 344N male rats did not affect splenic natural killer cell activity compared with intracerebroventricular saline-injected controls. SNC 80 also had no effect on concanavalin A-, anti-T cell receptor-, interleukin-2- and anti-T cell receptor + interleukin-2-induced splenic and thymic lymphocyte proliferation in most experiments. In some experiments, however, SNC 80 significantly (P < .01) caused a 41 to 93% increase of concanavalin A-, anti-T cell receptor-, interleukin-2- and anti-T cell receptor + interleukin-2-induced splenic lymphocyte proliferation compared to controls. Additionally, SNC 80 did not significantly affect splenic T cell or natural killer cell populations as measured by the expression of T cell receptoralphabeta, and T helper (CD4), T suppressor/cytotoxic (CD8) and natural killer cell surface markers. Finally, SNC 80 did not affect interferon-gamma- or lipopolysaccharide (LPS)-induced splenic nitric oxide, and LPS-induced tumor necrosis factor-alpha production by splenic macrophages. These results suggest that SNC 80 could be useful in the treatment of pain without suppressing immune function. However, the potential immunoenhancing properties of SNC 80 may be also valuable in immunocompromised individuals.

Animals↗
PubMed1997

The health status of women with cerebral palsy.

OBJECTIVE: To determine preliminary associations between collected health status variables of women with cerebral palsy (CP) residing in the community. DESIGN: Cross-sectional study using survey research. PARTICIPANTS: Sixty-three women residing in the community were administered the Telephone Questionnaire when contacted to arrange their visit to the study site located within the medical clinic of a local developmental services office. During the course of their visit to the study site, all 63 women completed the CP Study Protocol, in addition to the Mail-in Questionnaire upon completion of study participation. The women ranged in age from 20 to 74 years. MAIN OUTCOME MEASURES: Health status, consisting of four elements: (1) self-reported health status; (2) associated conditions; (3) secondary conditions; and (4) health behaviors (alcohol and tobacco use, physical activity, diet, and health care visit). RESULTS: Women with CP residing in community living arrangements perceived themselves as healthy. The majority of women did not smoke (98%), had not consumed alcohol in the previous month (95%), and ate a balanced diet (52%). Participants also reported engaging in common physical activities (83%) and stretching and doing range-of-motion exercises in the previous week (43%), and participation in aerobic exercise in the previous week (43%). Sixty-eight percent (41 of 60) of the women walked, and more than 50% of the women did not require assistance with activities of daily living. The ability to walk and the use of a wheelchair were associated with participation in the common physical activities. The women reported associated conditions of mental retardation (34%), learning disabilities (26%), and a seizure history (40%). Additionally, the women in the sample reported the occurrence of several secondary conditions common among individuals with CP, including pain (84%), hip and back deformities (59%), bowel problems (56%), bladder problems (49%), poor dental health (43%), and gastroesophageal reflux (28%). Poor dental health was associated with a history of seizures, and associations were also found between pain and mental retardation, and between gastroesophageal reflux and mental retardation. CONCLUSIONS: Women with CP residing in the community perceived themselves as healthy, and the observed health status measures (eg, self-reported health, associated conditions, secondary conditions, and selected health behaviors) support this concept. For the most part, independent relationships were found between several of these measures indicating no significant association among the variables. Where associations were found, however, such as between walking and participation in physical activity, further investigation is warranted for a better understanding of their ramifications in the design of health promotion activities for women with CP.

Activities of Daily Living↗
PubMed1997

Reevaluation of a weight-based heparin dosing nomogram: is institution-specific modification necessary?

OBJECTIVE: To compare a heparin dosing nomogram using an initial infusion rate of 18 units/kg/h with physician-directed heparin prescribing and with a modified version of the nomogram adjusted for institution-specific data. METHODS: During consecutive phases of this cohort study, patients' intravenous heparin therapies were initiated and adjusted by using one of the following three methods: (1) physician-directed dosing, (2) a body weight-based dosing nomogram with an initial infusion rate of 18 units/kg/h, and (3) a body weight-based dosing nomogram with an initial infusion rate determined by the median dose of heparin (in units/kg/h) required to achieve therapeutic activated partial thromboplastin times (aPTTs) during the first two phases. The time required to achieve therapeutic aPTTs as well as the percentage of initial aPTTs in the therapeutic range were compared for the three phases. RESULTS: The heparin dosing nomogram in which the initial infusion rate was adjusted for our individual institution resulted in a statistically shorter median time until aPTTs were in the therapeutic range than did either the physician-directed dosing or unmodified nomogram groups (6.1 h in the modified nomogram group, 10.5 h in the physician-directed group, 21.5 h in the unmodified nomogram group; p < 0.05 for all differences). Use of the institution-specific nomogram resulted in the greatest percentage of initial aPTTs in the therapeutic range (84% in the 13 units/kg/h nomogram group vs. 47% in the physician-directed group and 18% in the 18 units/kg/h nomogram group; p < 0.05 for all differences). CONCLUSIONS: Use of a heparin dosing nomogram with an initial infusion rate of 18 units/kg/h resulted in prolongation of the time to reach therapeutic aPTTs. By modifying the nomogram for use at an individual institution, we reduced the time to achieve therapeutic range of aPTTs while still reducing the likelihood of excessive anticoagulation of patients.

Aged↗
PubMed1996

The relevance of opioids and opioid receptors on immunocompetence and immune homeostasis.

Since the previous review on the role of opioids in the immune system, numerous investigative teams have contributed to the growing pool of information illustrating the tangible relationship between opioids and immune function, particularly as this association pertains to bacterial and viral pathogens. In addition, the recent cloning of both neural- and immune-derived opioid receptors will ultimately facilitate the identification of molecular events that are responsible for the immunomodulatory effects that are mediated by receptor ligation. Specifically, the administration of opioids in vivo can potentially affect the immune system either through direct interaction with receptors on the effector cells or indirectly, through the ligation of receptors found within the central nervous system. This indirect routing is hypothesized to involve secondary pathways including the hypothalamic pituitary adrenal (HPA) axis and the sympathetic nervous system ultimately resulting in immunomodulation. Consequently, a portion of this review addresses the recent data on leukocyte-derived opioid receptors and the potential immunoregulatory role relative to opiold receptors found within the central nervous system. In addition, recent observations on the effects of opioids and immunocompetence is reviewed from both a molecular and cellular perspective. Finally, the consequence of opioid exposure on the competence of the host immune system to microbial pathogens is summarized.

Amino Acid Sequence↗
PubMed1996

Morphine-induced alterations in antibody levels: receptor and immune mechanisms.

We have previously shown that an acute administration of morphine (10 mg/kg, i.v.) decreases IgG, but not IgM, antibody levels to antigen administered before morphine. Further, decreases in IgG were blocked by previous administration of naltrexone, indicating that receptor binding is critical to the decreased antibody levels. These studies investigated potential receptor and immune mechanisms for these effects. To investigate potential receptor mechanisms, the stereoselectivity and location of receptor binding was determined. The results of these experiments suggest morphine must bind stereoselectively to central sites to decrease antibody levels after antigen administration. To investigate potential immune mechanisms for these changes, antibody secreting cells (ASC) for keyhole limpet hemocyanin-specific IgG and IgM were enumerated. Morphine decreased ASC for IgG but increased ASC for IgM. Two pathways for the genetic switch from IgM to IgG production were investigated. One pathway requires interferon-gamma to stimulate IgM-secreting cells to switch to IgG2a-secreting cells. Another pathway requires interleukin-4 to stimulate IgM-secreting cells to switch to IgG1- secreting cells. IgG1 and IgG2a levels were measured to determine if these pathways were differentially affected and only IgG2a levels were decreased. Further, these decreases were accompanied by decreased IFN-gamma levels but not by altered numbers of splenocytes. These data indicate that morphine may alter the ability of ASC to switch from IgM to IgG2a production, possibly by reducing the availability of IFN-gamma.

Animals↗
PubMed1993

Inflammatory bowel disease: Part I. Clinical features and diagnosis.

Familial and epidemiologic studies of inflammatory bowel disease indicate a strong genetic predisposition that is modified by certain environmental factors. Abnormal submucosal immune activation may be important in the etiology of the disease. Yersinia enterocolitica infection, various "gay bowel syndromes" and other recently described enteric infections often mimic Crohn's disease. An initial barium study is useful in documenting the extent of disease and complications. Endoscopic biopsy confirms the surface appearance and histologic features of inflammatory bowel disease. Newer photodocumentation techniques are expected to improve the comparability of endoscopic observations. Complications of inflammatory bowel disease occur frequently, may involve any organ system and may precede the onset of bowel symptoms.

Colitis, Ulcerative↗
PubMed1993

Inflammatory bowel disease: Part II. Medical and surgical management.

Substantial advances have been made in the management of inflammatory bowel disease. Mesalamine and olsalazine are new anti-inflammatory agents that may serve as alternatives to corticosteroids and sulfasalazine, which have been the mainstays of medical therapy. These new agents are available in oral, enema and suppository forms. Brooke ileostomy remains the standard surgical treatment for advanced ulcerative pancolitis, but continent ileostomy procedures may be more cosmetically acceptable to selected patients.

Colitis, Ulcerative↗
PubMed1992

Recovery in hemiparkinsonian rats following intrastriatal implantation of activated leukocytes.

Behavioral improvement has been seen in hemiparkinsonian animals after surgical lesions of the denervated caudate nucleus. This study was designed to investigate the role of inflammatory cells in injury-induced recovery. A hemiparkinsonian syndrome was induced in rats by unilateral injections of 6-hydroxydopamine into the pars compacta of the substantia nigra. Phytohemagglutinin-stimulated rat peritoneal cells, predominantly T cells and macrophages, were stereotactically implanted in the lesioned caudate-putamen, and amphetamine-induced turning was used to assess recovery. Animals receiving implants of activated peritoneal cells showed a 47% decrease in amphetamine-induced turning 8 weeks after implantation, which was not seen in control or sham-operated animals. Immunocytochemistry revealed increased tyrosine hydroxylase reactive fibers in the leukocyte-implanted striatum. We conclude that implantation of activated leukocytes promotes functional recovery in hemiparkinsonian rats.

Animals↗
PubMed1992

Purification and characterization of naturally occurring benzodiazepine receptor ligands in rat and human brain.

Chemicals that are active at the benzodiazepine receptor (endozepines) are naturally present in the CNS. These substances are present in tissue from humans and animals and in plants and fungi. Using selective extraction protocols, HPLC purification, receptor binding displacement studies, and selective anti-benzodiazepine antibodies, we have identified six or seven peaks of endozepines in rat and human brain. All material could competitively displace [3H]flunitrazepam binding to cerebellar benzodiazepine binding sites. Two peaks also competitively displaced Ro 5-4864 binding to the mitochondrial benzodiazepine binding site. Total amounts of brain endozepines were estimated to be present in potentially physiological concentrations, based on their ability to displace [3H]flunitrazepam binding. Although endozepine peaks 1 and 2 had HPLC retention profiles similar to those of nordiazepam and diazepam, respectively, gas chromatography-mass spectrometry as well as high-performance TLC revealed biologically insignificant amounts of diazepam (less than 0.02 pg/g) and nordiazepam (less than 0.02 pg/g) in the purified material. Electrophysiologically, some purified endozepines positively modulated gamma-aminobutyric acid (GABA) action on Cl- conductance, monitored in patch-clamped cultured cortical neurons or in mammalian cells transfected with cDNA encoding various GABAA receptor subunits. These studies demonstrate that mammalian brains contain endozepines that could serve as potent endogenous positive allosteric modulators of GABAA receptors.

Allosteric Regulation↗
PubMed1991

(+)-cis-3-methylfentanyl and its analogs bind pseudoirreversibly to the mu opioid binding site: evidence for pseudoallosteric modulation.

Previous studies demonstrated that preincubation of membranes from the brain of the rat with 1 microM (+)-cis-3-methylfentanyl produced a wash-resistant inhibition of mu receptor binding. The present study was designed to: (1) determine the mechanism by which (+)-cis-3-methylfentanyl produced a wash-resistant inhibition of mu receptor binding, and (2) to generate a structure-activity study, using wash-resistant inhibition as the end-point. Pretreatment of membranes with 500 nM (+)-cis-3-methylfentanyl increased the Kd of binding sites for [3H]ohmefentanyl, without altering the Bmax. The increase in the Kd was only partially due to the presence of residual drug and was accompanied by an increase in the dissociation rate of the binding of [3H]ohmefentanyl. Therefore, pretreatment of membranes with (+)-cis-3-methylfentanyl resulted in a lower affinity interaction of [3H]ohmefentanyl with the mu binding site, consistent with a model postulating pseudoallosteric modulation of mu binding sites by (+)-cis-3-methylfentanyl and its analogs. The rank order of potencies for wash-resistant inhibition of the binding of [3H]6 beta-fluoro-6-desoxyoxymorphone or [3H]ohmefentanyl, was lofentanil greater than (+)-cis-3-methylfentanyl greater than ohmefentanyl greater than sufentanil. All other opioids tested (1 microM morphine, 1 microM naloxone, 1 microM fentanyl, 1 microM (+)-cyclazocine, 1 microM (-)-cis-3-methylfentanyl) did not act as wash-resistant inhibitors of mu binding sites. Although the pseudoirreversible IC50 of these agents did not correlate with their ED50 values for producing antinociception, after intravenous administration, the authors speculate that this property, termed "pseudoirreversible inhibition", might contribute to the extraordinary potency of (+)-cis-3-methylfentanyl and its analogs as antinociceptive agents.

Allosteric Regulation↗