Bar diagrams showing hepatic triglyceride content (A), plasma leptin (B), and insulin concentrations (C), and percentage of adipose visceral tissue (D), expressed as the mean±sd of 8 animals, for control and SLE mice at the weeks of sacrifice.

<p><b>E.</b> Bar diagrams showing the relative amount of P-Tyr-STAT-3 protein in liver tissue, expressed as the mean ± sd of values from 8 animals, from control (CT) and BWF1 (SLE) mice. The amount of protein loaded was confirmed by the Bradford method, and the uniformity of protein loading in each lane was assessed by determining the signal of β–actin as a control-loading protein.* <i>P</i><0.05, ** <i>P</i><0.01.</p

Genes whose expression was altered in visceral adipose tissue from 16-week old SLE <i>vs</i> CT mice.

<p>Genes whose expression was altered in visceral adipose tissue from 16-week old SLE <i>vs</i> CT mice.</p

BFWF1 mice, aged 36 weeks, showed increased kidney pathology.

<p>Hystological analysis of individual inflammatory (<b>A</b>) and glomerular hypercellularity scores (<b>B</b>) for CT and SLE mice, evaluated as described in the Material and Methods section. Representative photographs of renal sections from control (CT) (<b>C</b>) and BWF1 (SLE) (<b>D,E</b>) mice at the age of 36 weeks (H&E staining, light microscopy, original magnification ×40). Arrows indicate mesangial glomerular proliferation (<b>D</b>) and cellular extracapillary half-moon (<b>E</b>).</p

Bar diagrams showing the levels of AKT (A), IRS-1 (B) and RPS6K (C) protein in adipose tissue, and PPARγ (D), mTOR (E), and RPS6K (F) protein in liver tissue, expressed as the mean ± sd of values from 8 animals aged 16 weeks, for control (CT) and BWF1 (SLE) mice.

<p>The amount of protein loaded was confirmed by the Bradford method, and the uniformity of protein loading in each lane was assessed by determining the signal of β–actin as a control-loading protein. A representative autoradiography from a Western blot determination of two animals per group is shown. # <i>P</i> = 0.05, * <i>P</i><0.05, ** <i>P</i><0.01, *** <i>P</i><0.001.</p

A. Bar diagram showing solid food consumption, expressed as the mean±sd of g of pelleted diet consumed per day and animal, at different times (weeks) for control and SLE mice (8 animals per group).

<p><b>B.</b> Body weight, expressed as the mean±sd in g at the beginning of the study (week 6) and for control and SLE mice (8 animals per group) at the weeks of sacrifice. * <i>P</i><0.05.</p

Genes whose expression was altered in livers from 16-week old SLE <i>vs</i> CT mice.

<p>Genes whose expression was altered in livers from 16-week old SLE <i>vs</i> CT mice.</p

Bar diagrams showing IL-2 (A), IL-17 (B), MCP-1 (C), IL-4 (D), IL-5 (E), IL-10 (F), IL-13 (G), M-CSF (H), TNFα (I), and VEGF (J) concentrations in the supernatant of stimulated cultured splenocytes (see Material and Methods), expressed as the mean±sd of 8 cultures from separate animals, for control and SLE mice at week 36. * <i>P</i><0.05, ** <i>P</i><0.01.

<p>Bar diagrams showing IL-2 (A), IL-17 (B), MCP-1 (C), IL-4 (D), IL-5 (E), IL-10 (F), IL-13 (G), M-CSF (H), TNFα (I), and VEGF (J) concentrations in the supernatant of stimulated cultured splenocytes (see Material and Methods), expressed as the mean±sd of 8 cultures from separate animals, for control and SLE mice at week 36. * <i>P</i><0.05, ** <i>P</i><0.01.</p

Resilience to Pain-Related Depression in σ₁ Receptor Knockout Mice Is Associated with the Reversal of Pain-Induced Brain Changes in Affect-Related Genes

Mice lacking the σ1 receptor chaperone (σ1R–/–) are resilient to depressive-like behaviors secondary to neuropathic pain. Examining the resilience’s brain mechanisms could help develop conceptually novel therapeutic strategies. We explored the diminished motivation for a natural reinforcer (white chocolate) in the partial sciatic nerve ligation (PSNL) model in wild-type (WT) and σ1R–/– mice. In the same mice, we performed a comprehensive reverse transcription quantitative PCR (qPCR) analysis across ten brain regions of seven genes implicated in pain regulation and associated affective disorders, such as anxiety and depression. PSNL induced anhedonic-like behavior in WT but not in σ1R–/– mice. In WT mice, PSNL up-regulated dopamine transporter (DAT) and its rate-limiting enzyme, tyrosine hydroxylase (Th), in the ventral tegmental area (VTA) and periaqueductal gray (PAG) as well as the serotonin transporters (SERT) and its rate-limiting enzyme tryptophan hydroxylase 2 (Tph2) in VTA. In addition, μ-opioid receptor (MOR) and σ1R were up-regulated in PAG, and MOR was also elevated in the somatosensory cortex (SS) but down-regulated in the striatum (STR). Finally, increased BDNF was found in the medial prefrontal cortex (mPFC) and hypothalamus (HPT). Sham surgery also produced PSNL-like expression changes in VTA, HPT, and STR. Genetic deletion of the σ1R in mice submitted to PSNL or sham surgery prevented changes in the expression of most of these genes. σ1R is critically involved in the supraspinal gene expression changes produced by PSNL and sham surgery. The changes in gene expression observed in WT mice may be related to pain-related depression, and the absence of these changes observed in σ1R–/– mice may be related to resilience

Synthesis and Biological Evaluation of the 1‑Arylpyrazole Class of σ₁ Receptor Antagonists: Identification of 4‑{2-[5-Methyl-1-(naphthalen-2-yl)‑1<i>H</i>‑pyrazol-3-yloxy]ethyl}morpholine (S1RA, E‑52862)

The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent σ₁ receptor (σ₁R) antagonists are reported. The new compounds were evaluated in vitro in human σ₁R and guinea pig σ₂ receptor (σ₂R) binding assays. The nature of the pyrazole substituents was crucial for activity, and a basic amine was shown to be necessary, in accordance with known receptor pharmacophores. A wide variety of amines and spacer lengths between the amino and pyrazole groups were tolerated, but only the ethylenoxy spacer and small cyclic amines provided compounds with sufficient selectivity for σ₁R vs σ₂R. The most selective compounds were further profiled, and compound <b>28</b>, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1<i>H</i>-pyrazol-3-yloxy]­ethyl}­morpholine (S1RA, E-52862), which showed high activity in the mouse capsaicin model of neurogenic pain, emerged as the most interesting candidate. In addition, compound <b>28</b> exerted dose-dependent antinociceptive effects in several neuropathic pain models. This, together with its good physicochemical, safety, and ADME properties, led compound <b>28</b> to be selected as clinical candidate

Synthesis and Biological Evaluation of a New Series of Hexahydro‑2<i>H</i>‑pyrano[3,2‑<i>c</i>]quinolines as Novel Selective σ₁ Receptor Ligands

The synthesis and pharmacological activity of a new series of hexahydro-2<i>H</i>-pyrano­[3,2-<i>c</i>]­quinoline derivatives as potent σ₁ receptor (σ₁R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ₁R ligands, showed high selectivity over the σ₂ receptor (σ₂R). The activity was shown to reside in only one of the four possible diastereoisomers, which exhibited a perfect match with known σ₁R pharmacophores. A hit to lead program based on a high-throughput screening hit (<b>8a</b>) led to the identification of compound <b>32c</b>, with substantially improved activity and physicochemical properties. Compound <b>32c</b> also exhibited a good ADMET (absorption, distribution, metabolism, excretion, toxicity) profile and was identified as a σ₁R antagonist on the basis of its analgesic activity in the mouse capsaicin and formalin models of neurogenic pain