The non‐peptide GLP‐1 receptor agonist WB4‐24 blocks inflammatory nociception by stimulating β‐endorphin release from spinal microglia. (24th November 2014)

• Record Type: Journal Article
• Authors: Fan, Hui; Gong, Nian; Li, Teng‐Fei; Ma, Ai‐Niu; Wu, Xiao‐Yan; Wang, Ming‐Wei; Wang, Yong‐Xiang
• Is Part Of: British journal of pharmacology. Volume 172:Number 1(2015:Jan.)
• Page Start: 64
• Page End: 79
• Publication Date: 2014-11-24
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12895
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12895-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>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.</p> </sec> <sec id="bph12895-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>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.</p> </sec> <sec id="bph12895-sec-0003" sec-type="section"> <title>Key Results</title> <p>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.</p> </sec> <sec id="bph12895-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>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.</p> </sec> </abstract>