Intrathecal injection of adenosine 2A receptor agonists reversed neuropathic allodynia through protein kinase (PK)A/PKC signaling

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• 作者：Lisa C. Loram ; Frederick R. Taylor ; Keith A. Str ; Jacqueline A. Harrison ; Rachael RzasaLynn ; Paige Sholar ; Jayson Rieger ; Steven F. Maier ; Linda R. Watkins
• 关键词：Mechanical allodynia ; Protein kinase ; Interleukin-10 ; ATL313 ; Intrathecal ; Rats ; Microglia ; Astrocytes
• 刊名：Brain, Behavior, and Immunity
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：33
• 期：Complete
• 页码：112-122
• 全文大小：879 K

文摘

A single intrathecal dose of adenosine 2A receptor (A_2AR) agonist was previously reported to produce a multi-week reversal of allodynia in a chronic constriction injury (CCI) model of neuropathic pain. We aimed to determine if this long-term reversal was induced by A_2AR agonism versus more generalized across adenosine receptor subtypes, and begin to explore the intracellular signaling cascades involved. In addition, we sought to identify whether the enduring effect could be extended to other models of neuropathic pain. We tested an A₁R and A_2BR agonist in CCI and found the same long duration effect with A_2BR but not A₁R agonism. An A_2AR agonist (ATL313) produced a significant long-duration reversal of mechanical allodynia induced by long established CCI (administered 6 weeks after surgery), spinal nerve ligation and sciatic inflammatory neuropathy. To determine if ATL313 had a direct effect on glia, ATL313 was coadministered with lipopolysaccharide to neonatal microglia and astrocytes in vitro. ATL313 significantly attenuated TNF¦Á production in both microglia and astrocytes but had no effect on LPS induced IL-10. Protein kinase C significantly reversed the ATL313 effects on TNF¦Á in vitro in microglia and astrocytes, while a protein kinase A inhibitor only effected microglia. Both intrathecal PKA and PKC inhibitors significantly reversed the effect of the A_2AR agonist on neuropathic allodynia. Therefore, A_2AR agonists administered IT remain an exciting novel target for the treatment of neuropathic pain.