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

Predicting the Antinociceptive Efficacy of σ₁ Receptor Ligands by a Novel Receptor Fluorescence Resonance Energy Transfer (FRET) Based Biosensor

We have developed a novel methodology for monitoring the σ₁ receptor activation switch in living cells. Our assay uncovered the intrinsic nature of σ₁ 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 σ₁ receptor ligands