神经免疫信号传导是神经性疼痛的关键过程。临床研究表明,转运蛋白18kDa(TSPO),神经炎症的假定标志,在慢性疼痛患者的离散大脑区域上调。然而,没有临床前研究研究在神经性疼痛和对镇痛治疗的反应中TSPO在大脑中的动力学.我们使用正电子发射断层扫描计算机断层扫描(PET-CT)和[18F]-PBR06放射性配体来测量雄性和雌性大鼠坐骨神经慢性收缩损伤(CCI)后随时间变化的脑中TSPO水平。CCI后10周,TSPO表达在离散的大脑区域增加,包括内侧前额叶皮质,体感皮层,岛叶皮层,前扣带皮质,运动皮层,腹侧被盖区,杏仁核,中脑,pons,髓质,和伏隔核.在男性CCI后4周,TSPO在这些区域广泛上调,女性10周,尽管两性之间存在地区差异。使用免疫组织化学,我们证实了TSPO在这些区域的表达。我们进一步证明,TSPO主要在伏隔核核心的小胶质细胞中上调,和星形胶质细胞和内皮细胞在伏隔核壳。最后,我们测试了TSPO上调是否对富马酸二罗肟敏感,一种通过核因子E2相关因子2(Nrf2)诱导内源性抗氧化剂的药物。富马酸二罗肟酯减轻神经性疼痛并降低TSPO上调。我们的发现表明,TSPO在神经性疼痛发展的过程中上调,并通过对周围神经损伤的动物进行镇痛干预而得以解决。
Neuroimmune signaling is a key process underlying neuropathic pain. Clinical studies have demonstrated that 18 kDa translocator protein (TSPO), a putative marker of neuroinflammation, is upregulated in discrete brain regions of patients with chronic pain. However, no preclinical studies have investigated
TSPO dynamics in the brain in the context of neuropathic pain and in response to analgesic treatments. We used positron emission tomography-computed tomography (PET-CT) and [18F]-PBR06 radioligand to measure
TSPO levels in the brain across time after chronic constriction injury (CCI) of the sciatic nerve in both male and female rats. Up to 10 weeks post-CCI, TSPO expression was increased in discrete brain regions, including medial prefrontal cortex, somatosensory cortex, insular cortex, anterior cingulate cortex, motor cortex, ventral tegmental area, amygdala, midbrain, pons, medulla, and nucleus accumbens. TSPO was broadly upregulated across these regions at 4 weeks post CCI in males, and 10 weeks in females, though there were regional differences between the sexes. Using immunohistochemistry, we confirmed
TSPO expression in these regions. We further demonstrated that TSPO was upregulated principally in microglia in the nucleus accumbens core, and astrocytes and endothelial cells in the nucleus accumbens shell. Finally, we tested whether
TSPO upregulation was sensitive to diroximel fumarate, a drug that induces endogenous antioxidants via nuclear factor E2-related factor 2 (Nrf2). Diroximel fumarate alleviated neuropathic pain and reduced
TSPO upregulation. Our findings indicate that TSPO is upregulated over the course of neuropathic pain development and is resolved by an antinociceptive intervention in animals with peripheral nerve injury.