title: Anxiolytic-like effects of translocator protein (TSPO) ligand ZBD-2 in an animal model of chronic pain.
abstract: The activation of Translocator protein (18 kDa) (TSPO) has been demonstrated to mediate rapid anxiolytic efficacy in stress response and stress-related disorders. This protein is involved in the synthesis of endogenous neurosteroids that promote γ-aminobutyric acid (GABA)-mediated neurotransmission in the central neural system. However, little is known about the functions and the underlying mechanisms of TSPO in chronic pain-induced anxiety-like behaviors. The novel TSPO ligand N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl) acetamide (ZBD-2) was used in the present study. We found that ZBD-2 (0.15 or 1.5 mg/kg) significantly attenuated anxiety-like behaviors in mice with chronic inflammatory pain induced by hindpaw injection of complete Freund's adjuvant (CFA). However, the treatment did not alter the nociceptive threshold or inflammation in the hindpaw. Hindpaw injection of CFA induced the upregulation of TSPO, GluR1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and NR2B-containing N-methyl-D-aspartate (NMDA) receptors in the basolateral amygdala (BLA). ZBD-2 administration reversed the alterations of the abovementioned proteins in the BLA of the CFA-injected mice. Electrophysiological recording revealed that ZBD-2 could prevent an imbalance between excitatory and inhibitory transmissions in the BLA synapses of CFA-injected mice. Therefore, as the novel ligand of TSPO, ZBD-2 induced anxiolytic effects, but did not affect the nociceptive threshold of mice under chronic pain. The anxiolytic effects of ZBD-2 were related to the regulation of the balance between excitatory and inhibitory transmissions in the BLA.
authors.affiliation: Department of Orthopedics, Jinling Hospital, Clinical School of Nanjing, Second Military Medical University, Nanjing, 210002, China. 573631248@qq.com.
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China. zhentianzh@163.com.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tian
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China. gyy712@163.com.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China. ghl_0_1999@163.com.
authors.forename: Hong-Liang
authors.initials: HL
authors.lastname: Guo
authors.affiliation: Department of Orthopedics, Jinling Hospital, Clinical School of Nanjing, Second Military Medical University, Nanjing, 210002, China. kwb0521@163.com.
authors.forename: Wen-Bo
authors.initials: WB
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China. 348902986@qq.com.
authors.forename: Shuo
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China. dyt_sky@yahoo.com.cn.
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Den
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China. lixubo2005@126.com.
authors.forename: Xu-Bo
authors.initials: XB
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China. bingelfeng@hotmail.com.
authors.forename: Bing
authors.initials: B
authors.lastname: Feng
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China. 592599598@qq.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Feng
authors.affiliation: Department of Orthopedics, Jinling Hospital, Clinical School of Nanjing, Second Military Medical University, Nanjing, 210002, China. jnzhao2002@163.com.
authors.forename: Jian-Ning
authors.initials: JN
authors.lastname: Zhao
authors.affiliation: Department of Orthopedics, Jinling Hospital, Clinical School of Nanjing, Second Military Medical University, Nanjing, 210002, China. liug2002xian@hotmail.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China. minggao@fmmu.edu.cn.
authors.forename: Ming-Gao
authors.initials: MG
authors.lastname: Zhao
mesh_terms: D000081:Acetamides / Q000378:metabolism*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy; D059350:Chronic Pain / Q000188:drug therapy*; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000627:therapeutic use; D008297:Male; D008810:Mice, Inbred C57BL; D011688:Purinones / Q000378:metabolism*; D018079:Receptors, GABA / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission
chemical_list: D000081:Acetamides; D014151:Anti-Anxiety Agents; C463819:Bzrp protein, mouse; C000605004:N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; D011688:Purinones; D018079:Receptors, GABA; D005620:Freund's Adjuvant