4 research outputs found
Resilience to Pain-Related Depression in σ<sub>1</sub> 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
Predicting the Antinociceptive Efficacy of σ<sub>1</sub> Receptor Ligands by a Novel Receptor Fluorescence Resonance Energy Transfer (FRET) Based Biosensor
We
have developed a novel methodology for monitoring the σ<sub>1</sub> receptor activation switch in living cells. Our assay uncovered
the intrinsic nature of σ<sub>1</sub> receptor ligands by recording
the ligand-mediated conformational changes of this chaperone protein.
The change triggered by each ligand correlated well with its ability
to attenuate formalin induced nociception in an animal model of pain.
This tool may assist in predicting the antinociceptive efficacy of
σ<sub>1</sub> receptor ligands
Synthesis and Structure–Activity Relationship Study of a New Series of Selective σ<sub>1</sub> Receptor Ligands for the Treatment of Pain: 4‑Aminotriazoles
The
synthesis and pharmacological activity of a new series of 4-aminotriazoles
as potent σ<sub>1</sub> receptor (σ<sub>1</sub>R) ligands
are reported. The compounds were prepared using a 4–5-step
process, involving as a key step a click chemistry reaction between
ynamides and azides. The most active compounds exhibited nanomolar
potency for the σ<sub>1</sub>R, and the selectivity over the
σ<sub>2</sub>R was improved on decreasing the central amine
basicity. It was concluded that in order to achieve good σ<sub>1</sub>R potency a minimum lipophilicity was required, while limiting
to a defined range of cLog<i>P</i> avoided human ether-a-go-go-related
gene channel inhibition. This made the most interesting derivatives
to be concentrated in a narrow margin of lipophilicity. Among them,
compound <b>13g</b> exhibited the most potent in vivo antinociceptive
properties, which are indicative of its antagonist character
Synthesis and Biological Evaluation of the 1‑Arylpyrazole Class of σ<sub>1</sub> 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 σ<sub>1</sub> receptor (σ<sub>1</sub>R) antagonists are reported. The new compounds were evaluated
in vitro in human σ<sub>1</sub>R and guinea pig σ<sub>2</sub> receptor (σ<sub>2</sub>R) 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 σ<sub>1</sub>R vs σ<sub>2</sub>R. 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