title: Geranylgeranylacetone protects mice against morphine-induced hyperlocomotion, rewarding effect, and withdrawal syndrome.
abstract: There are few efficacious interventions to combat morphine dependence. Thioredoxin-1 (Trx-1) and heat shock protein 70 (Hsp70) are emerging as important modulators of neuronal function. They have been shown to be involved in cellular protective mechanisms against a variety of toxic stressors. This study was designed to investigate the effects of geranylgeranylacetone (GGA), a pharmacological inducer of Trx-1 and Hsp70, on morphine-induced hyperlocomotion, rewarding effect, and withdrawal syndrome. Trx-1 and Hsp70 expression was increased in the frontal cortex, hippocampus, ventral tegmental area, and nucleus accumbens of mice after GGA treatment. GGA administration reduced morphine-induced motor activity and inhibited conditioned place preference. GGA markedly attenuated the morphine-naloxone-induced withdrawal signs, including jumping, rearing, and forepaw tremor. Furthermore, the activation of cAMP-responsive element-binding protein and the expression of ΔFosB and cyclin-dependent kinase 5 were decreased in the nucleus accumbens by GGA treatment after morphine withdrawal. In the nucleus accumbens, GGA enhanced morphine-induced expression of Trx-1 and Hsp70 after morphine withdrawal. These results suggest that strengthening the expression of Trx-1 and Hsp70 in the brain by using noncytotoxic pharmacological inducers may provide a novel therapeutic strategy for morphine dependence. GGA could be a safe and novel therapeutic agent for morphine dependence.
authors.affiliation: Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming 650500, China.
authors.forename: Fu-Cheng
authors.initials: FC
authors.lastname: Luo
authors.forename: Lei
authors.initials: L
authors.lastname: Qi
authors.forename: Tao
authors.initials: T
authors.lastname: Lv
authors.forename: Sheng-Dong
authors.initials: SD
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakamura
authors.forename: Junji
authors.initials: J
authors.lastname: Yodoi
authors.forename: Jie
authors.initials: J
authors.lastname: Bai
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use* / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D004224:Diterpenes / Q000627:therapeutic use*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000633:toxicity*; D009021:Morphine Dependence / Q000517:prevention & control*; D012201:Reward; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D004224:Diterpenes; D018840:HSP70 Heat-Shock Proteins; D013879:Thioredoxins; D009020:Morphine; C031049:geranylgeranylacetone