Journal
JOURNAL OF NEUROSCIENCE
Volume 34, Issue 15, Pages 5322-5334Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4703-13.2014
Keywords
chronic pain; GLP-1 receptor; microglia
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Funding
- National Natural Science Foundation of China [81374000, 81202517]
- Doctoral Mentor Fund [20110073110062]
- Ministry of Education of China
- Shanghai Jiao Tong University
- SJTU School of Pharmacy
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This study aims to identify the inhibitory role of the spinal glucagon like peptide-1 receptor (GLP-1R) signaling in pain hypersensitivity and its mechanism of action in rats and mice. First, GLP-1Rs were identified to be specifically expressed on microglial cells in the spinal dorsal horn, and profoundly upregulated after peripheral nerve injury. In addition, intrathecal GLP-1R agonists GLP-1(7-36) and exenatide potently alleviated formalin-, peripheral nerve injury-, bone cancer-, and diabetes-induced hypersensitivity states by 60-90%, without affecting acute nociceptive responses. The antihypersensitive effects of exenatide and GLP-1 were completely prevented by GLP-1R antagonism and GLP-1R gene knockdown. Furthermore, exenatide evoked beta-endorphin release from both the spinal cord and cultured microglia. Exenatide antiallodynia was completely prevented by the microglial inhibitor minocycline, beta-endorphin antiserum, and opioid receptor antagonist naloxone. Our results illustrate a novel spinal dorsal horn microglial GLP-1R/beta-endorphin inhibitory pathway in a variety of pain hypersensitivity states.
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