title: Inhibition of Neuropathic Pain by a Single Intraperitoneal Injection of Diazepam in the Rat: Possible Role of Neurosteroids.
abstract: Diazepam binds with the same high affinity to the central benzodiazepine receptor (CBR) and the peripheral benzodiazepine receptor, which has been renamed translocator protein (TSPO). Both receptors could promote neurosteroid synthesis. In the present study, we investigated whether a single dose of diazepam could inhibit neuropathic pain induced by L5 spinal nerve ligation (L5 SNL), and whether CBR and TSPO mediated this effect. We found that a single intraperitoneal injection of diazepam 9 d after L5 SNL significantly depressed the established mechanical allodynia and thermal hyperalgesia, which persisted until the end of the experiments. Furthermore, the effects were mimicked by a single intraperitoneal injection of Ro5-4864, a specific TSPO agonist and pregnenolone, a neurosteroid precursor. In addition, we found that the inhibitory effect of diazepam was also completely blocked by pretreatment with a specific CBR antagonist, flumazenil. The effects of diazepam or Ro5-4864 on neuropathic pain were completely blocked by pretreatment with a neurosteroid synthesis inhibitor, aminoglutethimide (AMG). Finally, any one of the three drugs, diazepam, Ro5-4864 and pregnenolone, could reduce the activation of astrocytes and the production of interleukin-1beta (IL-1β) in the L5 spinal dorsal horn 14 d after L5 SNL. These results suggest that in addition to exerting effects on CBR, diazepam may inhibit neuropathic pain via TSPO, which promotes neurosteroid formation, subsequently reducing the activation of astrocytes and production of cytokines.
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, Guangdong, People's Republic of China.
authors.forename: Shu-Ling
authors.initials: SL
authors.lastname: Chen
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, Guangdong, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zang
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, Guangdong, People's Republic of China.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Zheng
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, Guangdong, People's Republic of China.
authors.forename: Xu-Hong
authors.initials: XH
authors.lastname: Wei
authors.affiliation: Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, Guangdong, People's Republic of China.
authors.forename: Xian-Guo
authors.initials: XG
authors.lastname: Liu
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002352:Carrier Proteins / Q000502:physiology; D003975:Diazepam / Q000008:administration & dosage*; D005442:Flumazenil / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D053583:Interleukin-1beta / Q000096:biosynthesis; D008297:Male; D009437:Neuralgia / Q000188:drug therapy*; D018377:Neurotransmitter Agents / Q000502:physiology*; D011284:Pregnenolone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology
chemical_list: D001570:Benzodiazepinones; D002352:Carrier Proteins; D053583:Interleukin-1beta; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; C028513:4'-chlorodiazepam; D005442:Flumazenil; D011284:Pregnenolone; D003975:Diazepam