Salvinorin A reduces mechanical allodynia and spinal neuronal hyperexcitability induced by peripheral formalin injection

ABSTRACT: BACKGROUND: Salvinorin A (SA), the main active component of Salvia Divinorum, is a non-nitrogenous kappa opioid receptor (KOR) agonist. It has been shown to reduce acute pain and to exert potent antinflammatory effects. This study assesses the effects and the mode of action of SA on formalin-induced persistent pain in mice. Specifically, the SA effects on long-term behavioural dysfuctions and changes in neuronal activity occurring at spinal level, after single peripheral formalin injection, have been investigated. Moreover, the involvement of microglial and glial cells in formalin-induced chronic pain condition and in SA-mediated effects has been evaluated. RESULTS: Formalin induced a significant decrease of mechanical withdrawal threshold at the injected and contralateral paw as well as an increase in the duration and frequency, and a rapid decrease in the onset of evoked activity of the nociceptive neurons 7 days after formalin injection. SA daily treatment significantly reduced mechanical allodynia in KOR and cannabinoid receptor 1 (CB1R) sensitive manner. SA treatment also normalized the spinal evoked activity. SA significantly reduced the formalin-mediated microglia and astrocytes activation and modulated pro and anti-inflammatory mediators in the spinal cord. CONCLUSION: SA is effective in reducing formalin-induced mechanical allodynia and spinal neuronal hyperactivity. Our findings suggest that SA reduces glial activation and contributes in the establishment of dysfunctions associated with chronic pain with mechanisms involving KOR and CB1R. SA may provide a new lead compound for developing anti-allodynic agents via KOR and CB1R activation.     

The role and molecular mechanism of D-aspartic acid in the release and synthesis of LH and testosterone in humans and rats

Background  

D-aspartic acid is an amino acid present in neuroendocrine tissues of invertebrates and vertebrates, including rats and humans. Here we investigated the effect of this amino acid on the release of LH and testosterone in the serum of humans and rats. Furthermore, we investigated the role of D-aspartate in the synthesis of LH and testosterone in the pituitary and testes of rats, and the molecular mechanisms by which this amino acid triggers its action.     

Emilin1 links TGF-beta maturation to blood pressure homeostasis

TGF-beta proteins are main regulators of blood vessel development and maintenance. Here, we report an unprecedented link between TGF-beta signaling and arterial hypertension based on the analysis of mice mutant for Emilin1, a cysteine-rich secreted glycoprotein expressed in the vascular tree. Emilin1 knockout animals display increased blood pressure, increased peripheral vascular resistance, and reduced vessel size. Mechanistically, we found that Emilin1 inhibits TGF-beta signaling by binding specifically to the proTGF-beta precursor and preventing its maturation by furin convertases in the extracellular space. In support of these findings, genetic inactivation of Emilin1 causes increased TGF-beta signaling in the vascular wall. Strikingly, high blood pressure observed in Emilin1 mutants is rescued to normal levels upon inactivation of a single TGF-beta1 allele. This study highlights the importance of modulation of TGF-beta availability in the pathogenesis of hypertension.     

p53 regulation orchestrates the TGF-beta response

Among its multiple functions, p53 is a critical regulator of TGF-beta responses. Sasai et al. (2008) now identify a new p53 inhibitory protein, XFDL156. During embryonic development, this factor is expressed in the ectoderm germ layer and maintains the pluripotency of ectodermal cells by inhibiting TGF-beta target genes that promote mesoderm specification.     

CD38 is associated with lipid rafts and upon receptor stimulation leads to Akt/protein kinase B and Erk activation in the absence of the CD3-zeta immune receptor tyrosine-based activation motifs.

T lymphocytes can be activated via the T cell receptor (TCR) or by triggering through a number of other cell surface structures, including the CD38 co-receptor molecule. Here, we show that in TCR+ T cells that express a CD3-zeta lacking the cytoplasmic domain, cross-linking with CD38- or CD3-specific monoclonal antibodies induces tyrosine phosphorylation of CD3-epsilon, zeta-associated protein-70, linker for activation of T cells, and Shc. Moreover, in these cells, anti-CD38 or anti-CD3 stimulation leads to protein kinase B/Akt and Erk activation, suggesting that the CD3-zeta-immunoreceptor tyrosine-based activation motifs are not required for CD38 signaling in T cells. Interestingly, in unstimulated T cells, lipid rafts are highly enriched in CD38, including the T cells lacking the cytoplasmic tail of CD3-zeta. Moreover, CD38 clustering by extensive cross-linking with an anti-CD38 monoclonal antibody and a secondary antibody leads to an increased resistance of CD38 to detergent solubilization, suggesting that CD38 is constitutively associated with membrane rafts. Consistent with this, cholesterol depletion with methyl-beta-cyclodextrin substantially reduces CD38-mediated Akt activation while enhancing CD38-mediated Erk activation. CD38/raft association may improve the signaling capabilities of CD38 via formation of protein/lipid domains to which signaling-competent molecules, such as immunoreceptor tyrosine-based activation motif-bearing CD3 molecules and protein-tyrosine kinases, are recruited.     

Nitrogen oxide emissions following wetting of dry soils in forest and pastures in Rondônia, Brazil

Rains at the end of the dry season can trigger increases in emissions of nitric oxide (NO) and nitrous oxide from forest and pasture soils in the Amazon Basin. The relative importance of the rain-stimulated emissions in the seasonal and annual budgets of these nitrogen gases for forests and pastures in the western Amazon is not well established. We measured soil emissions of NO and N₂O from a forest and two pastures, 11 and 26 years old, after a simulated rain event. Wetting the soil resulted in very small pulses of NO or N₂O from forest soils and no significant NO or N₂O pulses from the pastures. We estimated that in the forest, the amounts of each gas emitted from pulses during the dry to wet transition period represented 3.4% of the NO and 1.8% of the N₂O dry-season emissions, but amounted to less than 2% of the annual emissions of either gas. Total N oxide emissions of 5.6 kg N/ha/yr from the forest were nearly evenly divided between NO (42%) and N₂O (58%). The emissions of NO were evenly distributed over the wet and dry seasons, while over 84% N₂O fluxes occurred during the wet season.     

Carbohydrates in water-stable aggregates and particle size fractions of forested and cultivated soils in two contrasting tropical ecosystems

Information on changes in storage and loss of soil organic carbon (SOC) when tropical forests are converted to cropland is needed for evaluating soil structural degradation and for selecting appropriate sustainable soil management practices. We evaluated changes in SOC storage of organic carbon and acid-hydrolyzable carbohydrates content of aggregated classes and particle size fractions of adjacent forested and cultivated soils in eight agroecosystems from Ethiopian highlands and Nigerian lowlands. In all agroecosystems, SOC content was two to four times higher in the forested than the cultivated soils. Higher SOC content was found in Ethiopian (20.2–47.3 g.kg^–1) than Nigerian (12.0–24.0 g.kg^–1) forested soils. The magnitude of reduction in SOC and total carbohydrates with cultivation was soil-specific, being generally higher in the sandy than the clayey soils. The smaller aggregate classes (< 1.00 mm) and the sand-sized particles (2000–63 µm) of the forested soils were preferentially enriched in carbohydrates relative to larger aggregates (4.75–1.00 mm). Carbohydrates were more concentrated in the clay-size fraction of the forested than in that of the cultivated soils. Cultivation reduced aggregate stability, increased the proportions of the smaller size aggregates and their associated carbohydrates relative to the forested soils. The susceptibility of the cultivated soils to loss in structural stability reflected this initial aggregation which was greater in the more stable clayey than the fragile sandy soils. The aggregate stability of either the forested or the cultivated soil could not be accounted for by the levels of OC or total carbohydrates in the soil.