Activation of spinal glucagon-like peptide-1 receptors specifically suppresses pain hypersensitivity.
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 β-endorphin release from both the spinal cord and cultured microglia. Exenatide antiallodynia was completely prevented by the microglial inhibitor minocycline, β-endorphin antiserum, and opioid receptor antagonist naloxone. Our results illustrate a novel spinal dorsal horn microglial GLP-1R/β-endorphin inhibitory pathway in a variety of pain hypersensitivity states.
King's Laboratory, Shanghai Jiao Tong University School of Pharmacy, Shanghai 200240, China.
Nian
N
Gong
Qi
Q
Xiao
Bin
B
Zhu
Chang-Yue
CY
Zhang
Yan-Chao
YC
Wang
Hui
H
Fan
Ai-Niu
AN
Ma
Yong-Xiang
YX
Wang
D000818:Animals; D002478:Cells, Cultured; D000077270:Exenatide; D005934:Glucagon / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism* / Q000503:physiopathology; D017628:Microglia / Q000378:metabolism; D009437:Neuralgia / Q000378:metabolism* / Q000503:physiopathology; D059225:Nociception; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D020671:Posterior Horn Cells / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology; D001615:beta-Endorphin / Q000378:metabolism
C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; C082714:glucagon-like peptide 1 (7-36), Ala(36)-; D001615:beta-Endorphin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide
GLP-1 receptor; chronic pain; microglia