Single intrathecal administration of the transcription factor decoy AYX1 prevents acute and chronic pain after incisional, inflammatory, or neuropathic injury

详细信息    查看全文

• 作者：Julien Mamet ; Michael Klukinov ; Tony L. Yaksh ; Shelle A. Malkmus ; Samantha Williams ; Scott Harris ; Donald C. Manning ; Bradley K. Taylor ; Renee R. Donahue ; Frank Porreca ; Jennifer Y. Xie ; Janice Oyarzo ; Timothy J. Brennan ; Alberto Subieta ; William K. Schmidt ; David C. Yeomans
• 关键词：AYX1 ; Oligonucleotide ; Post-surgical pain ; Prevention ; Acute ; Chronic
• 刊名：Pain
• 出版年：February, 2014
• 年：2014
• 卷：155
• 期：2
• 页码：322-333
• 全文大小：1121 K

文摘

The persistence of pain after surgery increases the recovery interval from surgery to a normal quality of life. AYX1 is a DNA-decoy drug candidate designed to prevent post-surgical pain following a single intrathecal injection. Tissue injury causes a transient activation of the transcription factor EGR1 in the dorsal root ganglia-dorsal horn network, which then triggers changes in gene expression that induce neuronal hypersensitivity. AYX1 is a potent, specific inhibitor of EGR1 activity that mimics the genomic EGR1-binding sequence. Administered in the peri-operative period, AYX1 dose dependently prevents mechanical hypersensitivity in models of acute incisional (plantar), inflammatory (CFA), and chronic neuropathic pain (SNI) in rats. Furthermore, in a knee surgery model evaluating functional measures of postoperative pain, AYX1 improved weight-bearing incapacitance and spontaneous rearing compared to control. These data illustrate the potential clinical therapeutic benefits of AYX1 for preventing the transition of acute to chronic post-surgical pain.