Molecular signaling underlying bulleyaconitine A (BAA)-induced microglial expression of prodynorphin.
Bulleyaconitine (BAA) has been shown to possess antinociceptive activities by stimulation of dynorphin A release from spinal microglia. This study investigated its underlying signal transduction mechanisms. The data showed that (1) BAA treatment induced phosphorylation of CREB (rather than NF-κB) and prodynorphin expression in cultured primary microglia, and antiallodynia in neuropathy, which were totally inhibited by the CREB inhibitor KG-501; (2) BAA upregulated phosphorylation of p38 (but not ERK or JNK), and the p38 inhibitor SB203580 (but not ERK or JNK inhibitor) and p38β gene silencer siRNA/p38β (but not siRNA/p38α) completely blocked BAA-induced p38 phosphorylation and/or prodynorphin expression, and antiallodynia; (3) BAA stimulated cAMP production and PKA phosphorylation, and the adenylate cyclase inhibitor DDA and PKA inhibitor H-89 entirely antagonized BAA-induced prodynorphin expression and antiallodynia; (4) The Gs-protein inhibitor NF449 completely inhibited BAA-increased cAMP level, prodynorphin expression and antiallodynia, whereas the antagonists of noradrenergic, corticotrophin-releasing factor, A1 adenosine, formyl peptide, D1/D2 dopamine, and glucagon like-peptide-1 receptors failed to block BAA-induced antiallodynia. The data indicate that BAA-induced microglial expression of prodynorphin is mediated by activation of the cAMP-PKA-p38β-CREB signaling pathway, suggesting that its possible target is a Gs-protein-coupled receptor - "aconitine receptor", although the chemical identity is not illustrated.
King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
Teng-Fei
TF
Li
King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
Hai-Yun
HY
Wu
King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
Yi-Rui
YR
Wang
King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
Xin-Yan
XY
Li
King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
Yong-Xiang
YX
Wang
D000157:Aconitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004745:Enkephalins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D017628:Microglia / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D011498:Protein Precursors / Q000235:genetics*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D004745:Enkephalins; D011498:Protein Precursors; C052509:bulleyaconitine A; C033660:preproenkephalin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000157:Aconitine