title: The non-peptide GLP-1 receptor agonist WB4-24 blocks inflammatory nociception by stimulating β-endorphin release from spinal microglia.
abstract: OBJECTIVE
  Two peptide agonists of the glucagon-like peptide-1 (GLP-1) receptor, exenatide and GLP-1 itself, exert anti-hypersensitive effects in neuropathic, cancer and diabetic pain. In this study, we have assessed the anti-allodynic and anti-hyperalgesic effects of the non-peptide agonist WB4-24 in inflammatory nociception and the possible involvement of microglial β-endorphin and pro-inflammatory cytokines.
  
  
  METHODS
  We used rat models of inflammatory nociception induced by formalin, carrageenan or complete Freund's adjuvant (CFA), to test mechanical allodynia and thermal hyperalgesia. Expression of β-endorphin and pro-inflammatory cytokines was measured using real-time quantitative PCR and fluorescent immunoassays.
  
  
  RESULTS
  WB4-24 displaced the specific binding of exendin (9-39) in microglia. Single intrathecal injection of WB4-24 (0.3, 1, 3, 10, 30 and 100 μg) exerted dose-dependent, specific, anti-hypersensitive effects in acute and chronic inflammatory nociception induced by formalin, carrageenan and CFA, with a maximal inhibition of 60-80%. Spinal WB4-24 was not effective in altering nociceptive pain. Subcutaneous injection of WB4-24 was also antinociceptive in CFA-treated rats. WB4-24 evoked β-endorphin release but did not inhibit expression of pro-inflammatory cytokines in either the spinal cord of CFA-treated rats or cultured microglia stimulated by LPS. WB4-24 anti-allodynia was prevented by a microglial inhibitor, β-endorphin antiserum and a μ-opioid receptor antagonist.
  
  
  CONCLUSIONS
  Our results suggest that WB4-24 inhibits inflammatory nociception by releasing analgesic β-endorphin rather than inhibiting the expression of proalgesic pro-inflammatory cytokines in spinal microglia, and that the spinal GLP-1 receptor is a potential target molecule for the treatment of pain hypersensitivity including inflammatory nociception.
authors.affiliation: King's Lab, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Fan
authors.forename: Nian
authors.initials: N
authors.lastname: Gong
authors.forename: Teng-Fei
authors.initials: TF
authors.lastname: Li
authors.forename: Ai-Niu
authors.initials: AN
authors.lastname: Ma
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Wu
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Wang
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Wang
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002351:Carrageenan; D002478:Cells, Cultured; D003503:Cyclobutanes / Q000494:pharmacology* / Q000627:therapeutic use; D005557:Formaldehyde; D005620:Freund's Adjuvant; D000067757:Glucagon-Like Peptide-1 Receptor; D057809:HEK293 Cells; D006358:Hot Temperature; D006801:Humans; D006861:Hydrogen Peroxide; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D016877:Oxidants; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000819:agonists*; D013131:Spine / Q000166:cytology; D001615:beta-Endorphin / Q000378:metabolism*
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D003503:Cyclobutanes; C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D016877:Oxidants; D018027:Receptors, Glucagon; C000600953:WB4-24; D005557:Formaldehyde; D001615:beta-Endorphin; D002351:Carrageenan; D005620:Freund's Adjuvant; D006861:Hydrogen Peroxide