Griggs Ryan B, Donahue Renee R, Morgenweck Jenny, Grace Peter M, Sutton Amanda, Watkins Linda R, Taylor Bradley K
Department of Physiology, School of Medicine, University of Kentucky Medical Center, Lexington, KY, USA School of Science and Engineering, Neuroscience Graduate Program, Tulane University Health Sciences Center, New Orleans, LA, USA Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, CO, USA.
Pain. 2015 Mar;156(3):469-482. doi: 10.1097/01.j.pain.0000460333.79127.be.
Repeated administration of peroxisome proliferator-activated receptor gamma (PPARγ) agonists reduces neuropathic pain-like behavior and associated changes in glial activation in the spinal cord dorsal horn. As PPARγ is a nuclear receptor, sustained changes in gene expression are widely believed to be the mechanism of pain reduction. However, we recently reported that a single intrathecal (i.t.) injection of pioglitazone, a PPARγ agonist, reduced hyperalgesia within 30 minutes, a time frame that is typically less than that required for genomic mechanisms. To determine the very rapid antihyperalgesic actions of PPARγ activation, we administered pioglitazone to rats with spared nerve injury and evaluated hyperalgesia. Pioglitazone inhibited hyperalgesia within 5 minutes of injection, consistent with a nongenomic mechanism. Systemic or i.t. administration of GW9662, a PPARγ antagonist, inhibited the antihyperalgesic actions of intraperitoneal or i.t. pioglitazone, suggesting a spinal PPARγ-dependent mechanism. To further address the contribution of nongenomic mechanisms, we blocked new protein synthesis in the spinal cord with anisomycin. When coadministered intrathecally, anisomycin did not change pioglitazone antihyperalgesia at an early 7.5-minute time point, further supporting a rapid nongenomic mechanism. At later time points, anisomycin reduced pioglitazone antihyperalgesia, suggesting delayed recruitment of genomic mechanisms. Pioglitazone reduction of spared nerve injury-induced increases in GFAP expression occurred more rapidly than expected, within 60 minutes. We are the first to show that activation of spinal PPARγ rapidly reduces neuropathic pain independent of canonical genomic activity. We conclude that acute pioglitazone inhibits neuropathic pain in part by reducing astrocyte activation and through both genomic and nongenomic PPARγ mechanisms.
过氧化物酶体增殖物激活受体γ（PPARγ）激动剂的重复给药可减轻神经性疼痛样行为以及脊髓背角神经胶质细胞激活的相关变化。由于PPARγ是一种核受体，人们普遍认为基因表达的持续变化是疼痛减轻的机制。然而，我们最近报道，鞘内注射一次PPARγ激动剂吡格列酮可在30分钟内减轻痛觉过敏，这一时间框架通常短于基因组机制所需的时间。为了确定PPARγ激活的非常快速的抗痛觉过敏作用，我们给患有 spared nerve injury的大鼠施用吡格列酮并评估痛觉过敏。吡格列酮在注射后5分钟内抑制痛觉过敏，这与非基因组机制一致。全身性或鞘内注射PPARγ拮抗剂GW9662可抑制腹腔内或鞘内注射吡格列酮的抗痛觉过敏作用，提示脊髓PPARγ依赖性机制。为了进一步探讨非基因组机制的作用，我们用茴香霉素阻断脊髓中的新蛋白质合成。当鞘内共同给药时，茴香霉素在7.5分钟的早期时间点并未改变吡格列酮的抗痛觉过敏作用，进一步支持了快速的非基因组机制。在随后的时间点，茴香霉素降低了吡格列酮的抗痛觉过敏作用，提示基因组机制的延迟参与。吡格列酮减少 spared nerve injury诱导的GFAP表达增加的速度比预期更快，在60分钟内。我们首次表明脊髓PPARγ的激活可快速减轻神经性疼痛，而与经典的基因组活性无关。我们得出结论，急性吡格列酮部分通过减少星形胶质细胞激活以及通过基因组和非基因组PPARγ机制来抑制神经性疼痛。
