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The non‐peptide GLP ‐1 receptor agonist WB 4‐24 blocks inflammatory nociception by stimulating β ‐endorphin release from spinal microglia
Author(s) -
Fan Hui,
Gong Nian,
Li TengFei,
Ma AiNiu,
Wu XiaoYan,
Wang MingWei,
Wang YongXiang
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12895
Subject(s) - nociception , microglia , pharmacology , hyperalgesia , agonist , medicine , neuropathic pain , allodynia , receptor , inflammation
Background and Purpose 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 WB 4‐24 in inflammatory nociception and the possible involvement of microglial β‐endorphin and pro‐inflammatory cytokines. Experimental Approach We used rat models of inflammatory nociception induced by formalin, carrageenan or complete F reund'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. Key Results WB 4‐24 displaced the specific binding of exendin (9–39) in microglia. Single intrathecal injection of WB 4‐24 (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 WB 4‐24 was not effective in altering nociceptive pain. Subcutaneous injection of WB 4‐24 was also antinociceptive in CFA ‐treated rats. WB 4‐24 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. WB 4‐24 anti‐allodynia was prevented by a microglial inhibitor, β‐endorphin antiserum and a μ‐opioid receptor antagonist. Conclusions and Implications Our results suggest that WB 4‐24 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.