神经药理学报

神经药理学报 ›› 2018, Vol. 8 ›› Issue (4): 8-9.

• 2018年泰山学术论坛：神经精神科学学术峰会——Youth Academic Forum • 上一篇    下一篇

PDE4 Inhibitor Ameliorates Neuropathic Pain by Upregulating Spinal Connexin 43 Expression

ZHANG Fang-fang1，ZHOU Yan-memg1，WANG Hao1，GAO Shan1，WANG Lei1，TAN Rui1，DU Xian1，ZHAO Xiao-min1，ZHANG Han-ting1，2 *   

  1. 1.　 Institute of Pharmacology，Taishan Medical University，Taian，271016，China
    2.　 Departments of Behavioral Medicine & Psychiatry and Physiology，Pharmacology & Neuroscience，the
    Rockefeller Neurosciences Institute，West Virginia University Health Sciences Center，Morgantown，WV 26506，USA
  • 出版日期:2018-08-26 发布日期:2018-11-16
  • 通讯作者: ZHANG Han-ting，hzhang@hsc.wvu.edu （HT. ZHANG），15650512848@163.com （FF ZHANG）
  • 基金资助:

    Acknowledgements：This work was supported by the grants of china（ 2017-242，2017NS0237）.

PDE4 Inhibitor Ameliorates Neuropathic Pain by Upregulating Spinal Connexin 43 Expression

ZHANG Fang-fang1，ZHOU Yan-memg1，WANG Hao1，GAO Shan1，WANG Lei1，TAN Rui1，DU Xian1，ZHAO Xiao-min1，ZHANG Han-ting1，2 *   

  1. 1.　 Institute of Pharmacology，Taishan Medical University，Taian，271016，China
    2.　 Departments of Behavioral Medicine & Psychiatry and Physiology，Pharmacology & Neuroscience，the
    Rockefeller Neurosciences Institute，West Virginia University Health Sciences Center，Morgantown，WV 26506，USA
  • Online:2018-08-26 Published:2018-11-16
  • Contact: ZHANG Han-ting，hzhang@hsc.wvu.edu （HT. ZHANG），15650512848@163.com （FF ZHANG）
  • Supported by:

    Acknowledgements：This work was supported by the grants of china（ 2017-242，2017NS0237）.

摘要： Objective: Peripheral nerve injury downregulates connexin43 (Cx43) expression in spinal astrocytes. Therefore, restoration of spinal astrocyte Cx43 expression to normal levels could lead to the reduction of nerve injury-induced pain. It has been shown that inhibitors of phosphodiesterase-4 (PDE4), an enzyme catalyzing the hydrolysis of cyclic AMP (cAMP), reverse mechanical pain in mice with neuropathic pain. However, the antinociceptive mechanism remains unclear. In the present study, we evaluated the antinociceptive effect of PDE4 inhibitors and demonstrated a novel mechanism by which PDE4 mediates nociception via Cx43 in spinal astrocytes. Methods: The effects of PDE4 inhibitors on neuropathic pain and Cx43 expression in spinal astrocytes were evaluated in mice with partial sciatic nerve ligation (PSNL). Results: Single or repeated, intraperitoneal treatment with the selective PDE4 inhibitor rolipram or roflumilast of mice with PSNL significantly reduced mechanical hypersensitivity. This was mimicked by intrathecal administration of rolipram or roflumilast. In addition, repeated intrathecal treatment with rolipram or roflumilast of mice with PSNL completely prevented the downregulation of Cx43 expression in the spinal dorsal horn. Conclusion: The results suggest that PDE4 inhibitors ameliorate neuropathic pain, which is mediated by a spinal mechanism through the restoration of spinal Cx43 expression.

关键词: phosphodiesterase-4 （PDE4）, connexin43, rolipram, roflumilast, neuropathic pain

Abstract: Objective: Peripheral nerve injury downregulates connexin43 (Cx43) expression in spinal astrocytes. Therefore, restoration of spinal astrocyte Cx43 expression to normal levels could lead to the reduction of nerve injury-induced pain. It has been shown that inhibitors of phosphodiesterase-4 (PDE4), an enzyme catalyzing the hydrolysis of cyclic AMP (cAMP), reverse mechanical pain in mice with neuropathic pain. However, the antinociceptive mechanism remains unclear. In the present study, we evaluated the antinociceptive effect of PDE4 inhibitors and demonstrated a novel mechanism by which PDE4 mediates nociception via Cx43 in spinal astrocytes. Methods: The effects of PDE4 inhibitors on neuropathic pain and Cx43 expression in spinal astrocytes were evaluated in mice with partial sciatic nerve ligation (PSNL). Results: Single or repeated, intraperitoneal treatment with the selective PDE4 inhibitor rolipram or roflumilast of mice with PSNL significantly reduced mechanical hypersensitivity. This was mimicked by intrathecal administration of rolipram or roflumilast. In addition, repeated intrathecal treatment with rolipram or roflumilast of mice with PSNL completely prevented the downregulation of Cx43 expression in the spinal dorsal horn. Conclusion: The results suggest that PDE4 inhibitors ameliorate neuropathic pain, which is mediated by a spinal mechanism through the restoration of spinal Cx43 expression.

Key words: phosphodiesterase-4 （PDE4）, connexin43, rolipram, roflumilast, neuropathic pain