title: Spinal microglial P2X4 receptor-brain-derived neurotrophic factor signaling regulates nicotine withdrawal-induced hyperalgesia.
abstract: Nicotine withdrawal (NTW) has been shown to increase pain sensitivity. However, the pathogenesis of NTW-induced hyperalgesia syndrome is unknown. Microglial activation, with increased expression of the P2X4 receptor (P2X4R) and brain-derived neurotrophic factor (BDNF) as important markers, is associated with hyperalgesia; therefore, these markers may represent an unprecedented target to prevent hyperalgesia. In this study, we explored the contributions of spinal microglial P2X4R-BDNF signaling in NTW-induced hyperalgesia. Immunohistochemical analysis showed that spinal microglia were activated and that the P2X4R level was increased and colocalized with ionized calcium-binding adapter molecule 1 in NTW-induced hyperalgesia. Furthermore, we showed that microglial activation with NTW resulted in an increased expression of spinal P2X4R and an elevated release of BDNF. Intrathecal minocycline (a specific inhibitor of microglial activation) reversed thermal hyperalgesia as well as increased the spinal microglial P2X4R and BDNF levels induced by NTW. To the best of our knowledge, the present study provides evidence that spinal microglial P2X4R-BDNF signaling is critical for the development of NTW-induced hyperalgesia.
authors.affiliation: aJiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu Province bDepartment of Anesthesiology, Liaocheng People's Hospital, Liaocheng, Shandong cDepartment of Medicine, Hebei North University, Zhangjiakou, Hebei, China.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Zhang
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Xu
authors.forename: Chengbao
authors.initials: C
authors.lastname: Li
authors.forename: Wenchao
authors.initials: W
authors.lastname: Zhu
authors.forename: Shanshan
authors.initials: S
authors.lastname: Wu
authors.forename: Ailan
authors.initials: A
authors.lastname: Yu
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Ding
authors.forename: Qinghe
authors.initials: Q
authors.lastname: Wang
authors.forename: Zongwang
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008911:Minocycline / Q000494:pharmacology; D009538:Nicotine / Q000633:toxicity; D018722:Nicotinic Agonists / Q000633:toxicity; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D017207:Rats, Sprague-Dawley; D058848:Receptors, Purinergic P2X4 / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: C100745:Aif1 protein, rat; D018712:Analgesics, Non-Narcotic; D019208:Brain-Derived Neurotrophic Factor; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D018722:Nicotinic Agonists; D058848:Receptors, Purinergic P2X4; D009538:Nicotine; D008911:Minocycline