Opioid-like discriminative stimulus properties of benzomorphans in the pigeon: stereospecificity and differential substitution patterns

Pigeons were trained to discriminate the kappa-opioid agonist bremazocine (BREM) or the mu-opioid agonist fentanyl (FENT) from water. During tests of stimulus substitution, FENT and BREM failed to substitute for each other. The (-)-isomers of cyclazocine, pentazocine and ketocyclazocine substituted for the FENT but not the BREM stimulus. The (+)-isomers of these compounds, as well as the isomers of nallylnormetazocine, failed to substitute for either the FENT or BREM stimulus. In FENT- and BREM-trained pigeons, the (-)-isomers of cyclazocine, pentazocine, nallylnormetazocine and ketocyclazocine were more potent than their respective(+)-isomers in decreasing rates of responding. These results indicate that in the pigeon there is an isomeric separation of the discriminative stimulus properties of cyclazocine, pentazocine and ketocyclazocine and that the FENT-like stimulus effects of these drugs reside in their (-)-isomers. In addition, the present findings establish further that the classification of the discriminative stimulus effects of mu and kappa opioid compounds in the pigeon differ from those in rat and monkey.     

Integrating Survey and Molecular Approaches to Better Understand Wildlife Disease Ecology

Infectious wildlife diseases have enormous global impacts, leading to human pandemics, global biodiversity declines and socio-economic hardship. Understanding how infection persists and is transmitted in wildlife is critical for managing diseases, but our understanding is limited. Our study aim was to better understand how infectious disease persists in wildlife populations by integrating genetics, ecology and epidemiology approaches. Specifically, we aimed to determine whether environmental or host factors were stronger drivers of Salmonella persistence or transmission within a remote and isolated wild pig (Sus scrofa) population. We determined the Salmonella infection status of wild pigs. Salmonella isolates were genotyped and a range of data was collected on putative risk factors for Salmonella transmission. We a priori identified several plausible biological hypotheses for Salmonella prevalence (cross sectional study design) versus transmission (molecular case series study design) and fit the data to these models. There were 543 wild pig Salmonella observations, sampled at 93 unique locations. Salmonella prevalence was 41% (95% confidence interval [CI]: 37–45%). The median Salmonella DICE coefficient (or Salmonella genetic similarity) was 52% (interquartile range [IQR]: 42–62%). Using the traditional cross sectional prevalence study design, the only supported model was based on the hypothesis that abundance of available ecological resources determines Salmonella prevalence in wild pigs. In the molecular study design, spatial proximity and herd membership as well as some individual risk factors (sex, condition score and relative density) determined transmission between pigs. Traditional cross sectional surveys and molecular epidemiological approaches are complementary and together can enhance understanding of disease ecology: abundance of ecological resources critical for wildlife influences Salmonella prevalence, whereas Salmonella transmission is driven by local spatial, social, density and individual factors, rather than resources. This enhanced understanding has implications for the control of diseases in wildlife populations. Attempts to manage wildlife disease using simplistic density approaches do not acknowledge the complexity of disease ecology.     

Germinal center alloantibody responses are mediated exclusively by indirect-pathway CD4 T follicular helper cells

The durable alloantibody responses that develop in organ transplant patients indicate long-lived plasma cell output from T-dependent germinal centers (GCs), but which of the two pathways of CD4 T cell allorecognition is responsible for generating allospecific T follicular helper cells remains unclear. This was addressed by reconstituting T cell-deficient mice with monoclonal populations of TCR-transgenic CD4 T cells that recognized alloantigen only as conformationally intact protein (direct pathway) or only as self-restricted allopeptide (indirect pathway) and then assessing the alloantibody response to a heart graft. Recipients reconstituted with indirect-pathway CD4 T cells developed long-lasting IgG alloantibody responses, with splenic GCs and allospecific bone marrow plasma cells readily detectable 50 d after heart transplantation. Differentiation of the transferred CD4 T cells into T follicular helper cells was confirmed by follicular localization and by acquisition of signature phenotype. In contrast, IgG alloantibody was not detectable in recipient mice reconstituted with direct-pathway CD4 T cells. Neither prolongation of the response by preventing NK cell killing of donor dendritic cells nor prior immunization to develop CD4 T cell memory altered the inability of the direct pathway to provide allospecific B cell help. CD4 T cell help for GC alloantibody responses is provided exclusively via the indirect-allorecognition pathway.     

The response of German cockroaches to toxic baits:strain differences and the effects of selection pressure

Strain differences in the response of German cockroaches to toxic baits and their potential to evolve resistance to them was evaluated in choice tests. Percentage bait consumption (amount of bait consumed divided by total food consumed) was used to estimate relative attractancy/repellency of the baits. One strain apparently had low level resistance to abamectin, but no evidence of resistance was found in other strains tested with either Roach Ender or a gel bait (abamectin-based baits). Incipient behavioral resistance occurred in two strains selected for three generations with Roach Ender; a stronger response in a strain selected with the gel bait is attributed to the development of behavioral resistance. Baygon bait was highly repellent. Low level resistance to propoxur caused a large decrease in mortality compared with susceptible strains. Strong behavioral resistance developed in strains selected with Stapleton's Magnetic Roach Food.     

Distinct but overlapping expression patterns of two vertebrate slit homologs implies functional roles in CNS development and organogenesis.

The Drosophila slit gene (sli) encodes a secreted leucine-rich repeat-containing protein (slit) expressed by the midline glial cells and required for normal neural development. A putative human sli homolog, SLIT1, has previously been identified by EST database scanning. We have isolated a second human sli homolog, SLIT2, and its murine homolog Slit2. Both SLIT1 and SLIT2 proteins show approximately 40% amino acid identity to slit and 60% identity to each other. In mice, both genes are expressed during CNS development in the floor plate, roof plate and developing motor neurons. As floor plate represents the vertebrate equivalent to the midline glial cells, we predict a conservation of function for these vertebrate homologs. Each gene shows additional but distinct sites of expression outside the CNS suggesting a variety of functions for these proteins.     

Modulation of delta opioid agonist-induced antinociception by repeated morphine pretreatment in rhesus monkeys

AimsRepeated treatment with morphine increases antinociceptive effects of delta opioid agonists in rodents by a mechanism that may involve increased cell-surface expression of delta receptors. The present study evaluated effects of repeated morphine treatment on behavioral effects of the delta agonist SNC80 and the mu agonist fentanyl in rhesus monkeys.Main methodsIn an assay of schedule-controlled responding, three monkeys responded for food reinforcement under a fixed-ratio 30 schedule. In an assay of thermal nociception, tail-withdrawal latencies were evaluated in three monkeys using thermal stimulus intensities of 48 and 54 °C. In both assays, the effects of SNC80 (0.032–3.2 mg/kg) and fentanyl (0.001–0.056 mg/kg) were evaluated after repeated treatment with saline or a regimen of morphine doses modeled on the regimen that enhanced delta agonist antinociception and apparent delta receptor availability in previous rodent studies.Key findingsBoth SNC80 and fentanyl dose-dependently decreased rates of schedule-controlled responding, and repeated morphine treatment did not significantly alter these effects. In the assay of thermal nociception, SNC80 had little effect on tail-withdrawal latencies from water heated to 48 or 54 °C, whereas fentanyl increased tail-withdrawal latencies at both temperatures. Repeated morphine tended to increase the antinociceptive effects of SNC80 and to decrease the antinociceptive effects of fentanyl, but these effects of repeated morphine were small and were significant only at the higher stimulus intensity (54 °C).SignificanceThese results provide limited support for the proposition that prior stimulation of mu receptors selectively increases the antinociceptive effects of delta agonists in rhesus monkeys.