2024-01-30 テキサス大学オースチン校(UT Austin)
◆研究者たちは、マウスの試験で神経障害性疼痛に関与すると示されたタンパク質に結合する分子を発見し、その新しい化合物(FEM-1689)が効果的な鎮痛薬であり、オピオイド受容体に結合しないことがわかりました。この新薬は感受性を減少させるだけでなく、体の統合ストレス応答(ISR)を調整し、ISRが疾患に対応する体のシグナルをコントロールします。オピオイド依存性が関連する既存の鎮痛薬への代替手段として期待されています。
<関連情報>
- https://news.utexas.edu/2024/01/30/researchers-uncover-potential-non-opioid-treatment-for-chronic-pain/
- https://www.pnas.org/doi/10.1073/pnas.2306090120
高度に特異的なσ2R/TMEM97リガンドFEM-1689は神経障害性疼痛を緩和し、統合ストレス反応を抑制する Highly specific σ2R/TMEM97 ligand FEM-1689 alleviates neuropathic pain and inhibits the integrated stress response
Muhammad Saad Yousuf, James J. Sahn, Hongfen Yang, +13, and Theodore J. Price
Proceedings of the National Academy of Sciences Published:December 20, 2023
DOI:https://doi.org/10.1073/pnas.2306090120
Significance
Neuropathic pain is a major medical problem that is poorly treated with existing therapeutics. Our findings demonstrate that targeting σ2R/TMEM97 with a modulator reduces pain hypersensitivity in a mouse model with exquisite selectivity. We also identify integrated stress response (ISR) inhibition as a potential mechanism of action that links the receptor to cellular signaling events that have preclinical and clinical validation for pain relief. Our work suggests that σ2R/TMEM97 can be selectively engaged by specific small molecules to produce ISR inhibition in a subset of cells that are critical for neuropathic pain. σ2R/TMEM97-targeted therapeutics thus have the potential to offer effective pain relief without engagement of opioid receptors.
Abstract
The sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal antinociceptive effect is approximately 24 h following dosing. We sought to understand this unique antineuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout mice for Tmem97, we find that a σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce antinociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain.
