Anxiolytic-like effects of translocator protein (TSPO) ligand ZBD-2 in an animal model of chronic pain

Molecular Pain

Ming-gao Zhao¹  Gang Liu²  Jian-ning Zhao²  Dan Feng¹  Bing Feng¹  Xu-bo Li¹  Ya-ting Den¹  Shuo Li¹  Wen-bo Kang²  Hong-liang Guo¹  Yan-yan Guo¹  Zhen Tian¹  Dong-sheng Wang² 

[1] Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an 710032, China;Department of Orthopedics, Jinling Hospital, Clinical School of Nanjing, Second Military Medical University, Nanjing 210002, China

关键词: Amygdala;    Pain;    Anxiety;    kDa);    Translocator protein (18 ;   

Others  :  1161764
DOI  :  10.1186/s12990-015-0013-6

 received in 2014-11-18, accepted in 2015-03-15,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Wang et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Papadopoulos V, Lecanu L, Brown RC, Han Z, Yao ZX: Peripheral-type benzodiazepine receptor in neurosteroid biosynthesis, neuropathology and neurological disorders. Neuroscience 2006, 138:749-56.
• [2]Anholt RR, Pedersen PL, De Souza EB, Snyder SH: The peripheral-type benzodiazepine receptor: localization to the mitochondrial outer membrane. J Biol Chem 1986, 261:576-83.
• [3]Rupprecht R, Rammes G, Eser D, Baghai TC, Schule C, Nothdurfter C, et al.: Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects. Science 2009, 325:490-3.
• [4]Zhang LM, Zhao N, Guo WZ, Jin ZL, Qiu ZK, Chen HX, et al.: Antidepressant-like and anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa). Neuropharmacology 2014, 81:116-25.
• [5]Kita A, Kohayakawa H, Kinoshita T, Ochi Y, Nakamichi K, Kurumiya S, et al.: Antianxiety and antidepressant-like effects of AC-5216, a novel mitochondrial benzodiazepine receptor ligand. Br J Pharmacol 2004, 142:1059-72.
• [6]Droogleever Fortuyn HA, van Broekhoven F, Span PN, Backstrom T, Zitman FG, Verkes RJ: Effects of PhD examination stress on allopregnanolone and cortisol plasma levels and peripheral benzodiazepine receptor density. Psychoneuroendocrinol 2004, 29:1341-4.
• [7]Girard C, Liu S, Adams D, Lacroix C, Sineus M, Boucher C, et al.: Axonal regeneration and neuroinflammation: roles for the translocator protein 18 kDa. J Neuroendocrinol 2012, 24:71-81.
• [8]Millan MJ: The induction of pain: an integrative review. Prog Neurobiol 1999, 57:1-164.
• [9]Demyttenaere K, Bruffaerts R, Lee S, Posada-Villa J, Kovess V, Angermeyer MC, et al.: Mental disorders among persons with chronic back or neck pain: results from the world mental health surveys. Pain 2007, 129:332-42.
• [10]Parent AJ, Beaudet N, Beaudry H, Bergeron J, Berube P, Drolet G, et al.: Increased anxiety-like behaviors in rats experiencing chronic inflammatory pain. Behav Brain Res 2012, 229:160-7.
• [11]Blackburn-Munro G, Blackburn-Munro RE: Chronic pain, chronic stress and depression: coincidence or consequence? J Neuroendocrinol 2001, 13:1009-23.
• [12]Narita M, Kaneko C, Miyoshi K, Nagumo Y, Kuzumaki N, Nakajima M, et al.: Chronic pain induces anxiety with concomitant changes in opioidergic function in the amygdala. Neuropsychopharmacol 2006, 31:739-50.
• [13]Hernstadt H, Wang S, Lim G, Mao J: Spinal translocator protein (TSPO) modulates pain behavior in rats with CFA-induced monoarthritis. Brain Res 2009, 1286:42-52.
• [14]Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, et al.: NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J Neurosci 2007, 27:2846-57.
• [15]Rainnie DG, Bergeron R, Sajdyk TJ, Patil M, Gehlert DR, Shekhar A: Corticotrophin releasing factor-induced synaptic plasticity in the amygdala translates stress into emotional disorders. J Neurosci 2004, 24:3471-9.
• [16]Tasan RO, Nguyen NK, Weger S, Sartori SB, Singewald N, Heilbronn R, et al.: The central and basolateral amygdala are critical sites of neuropeptide Y/Y2 receptor-mediated regulation of anxiety and depression. J Neurosci 2010, 30:6282-90.
• [17]Ehrlich I, Humeau Y, Grenier F, Ciocchi S, Herry C, Luthi A: Amygdala inhibitory circuits and the control of fear memory. Neuron 2009, 62:757-71.
• [18]Wang SH, de Oliveira AL, Nader K: Cellular and systems mechanisms of memory strength as a constraint on auditory fear reconsolidation. Nat Neurosci 2009, 12:905-12.
• [19]Wu LJ, Kim SS, Zhuo M: Molecular targets of anxiety: from membrane to nucleus. Neurochem Res 2008, 33:1925-32.
• [20]Tian Z, Wang Y, Zhang N, Guo YY, Feng B, Liu SB, et al.: Estrogen receptor GPR30 exerts anxiolytic effects by maintaining the balance between GABAergic and glutamatergic transmission in the basolateral amygdala of ovariectomized mice after stress. Psychoneuroendocrinol 2013, 38:2218-33.
• [21]Da Settimo F, Simorini F, Taliani S, La Motta C, Marini AM, Salerno S, et al.: Anxiolytic-like effects of N, N-dialkyl-2-phenylindol-3-ylglyoxylamides by modulation of translocator protein promoting neurosteroid biosynthesis. J Med Chem 2008, 51:5798-806.
• [22]Bitran D, Foley M, Audette D, Leslie N, Frye CA: Activation of peripheral mitochondrial benzodiazepine receptors in the hippocampus stimulates allopregnanolone synthesis and produces anxiolytic-like effects in the rat. Psychopharmacology (Berl) 2000, 151:64-71.
• [23]Chen MK, Guilarte TR: Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair. Pharmacol Ther 2008, 118:1-17.
• [24]Keefe FJ, Rumble ME, Scipio CD, Giordano LA, Perri LM: Psychological aspects of persistent pain: current state of the science. J Pain 2004, 5:195-211.
• [25]Rupprecht R, Papadopoulos V, Rammes G, Baghai TC, Fan J, Akula N, et al.: Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov 2010, 9:971-88.
• [26]Veiga S, Azcoitia I, Garcia-Segura LM: Ro5-4864, a peripheral benzodiazepine receptor ligand, reduces reactive gliosis and protects hippocampal hilar neurons from kainic acid excitotoxicity. J Neurosci Res 2005, 80:129-37.
• [27]Vowinckel E, Reutens D, Becher B, Verge G, Evans A, Owens T, et al.: PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neurosci Res 1997, 50:345-53.
• [28]Chua SW, Kassiou M, Ittner LM: The translocator protein as a drug target in Alzheimer’s disease. Expert Rev Neurother 2014, 14:439-48.
• [29]Zhang LM, Qiu ZK, Zhao N, Chen HX, Liu YQ, Xu JP, et al.: Anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) in animal models of post-traumatic stress disorder. Int J Neuropsychopharmacol 2014, 17:1659-69.
• [30]Qiu ZK, Zhang LM, Zhao N, Chen HX, Zhang YZ, Liu YQ, et al.: Repeated administration of AC-5216, a ligand for the 18 kDa translocator protein, improves behavioral deficits in a mouse model of post-traumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry 2013, 45:40-6.
• [31]DalBo S, Nardi GM, Ferrara P, Ribeiro-do-Valle RM, Farges RC: Antinociceptive effects of peripheral benzodiazepine receptors. Pharmacology 2004, 70:188-94.
• [32]Wei XH, Wei X, Chen FY, Zang Y, Xin WJ, Pang RP, et al.: The upregulation of translocator protein (18 kDa) promotes recovery from neuropathic pain in rats. J Neurosci 2013, 33:1540-51.
• [33]Diaz MR, Chappell AM, Christian DT, Anderson NJ, McCool BA: Dopamine D3-like receptors modulate anxiety-like behavior and regulate GABAergic transmission in the rat lateral/basolateral amygdala. Neuropsychopharmacol 2011, 36:1090-103.
• [34]Tran L, Greenwood-Van Meerveld B: Lateralized amygdala activation: importance in the regulation of anxiety and pain behavior. Physiol Behav 2012, 105:371-5.
• [35]Engin E, Liu J, Rudolph U: alpha2-containing GABA (A) receptors: a target for the development of novel treatment strategies for CNS disorders. Pharmacol Ther 2012, 136:142-52.
• [36]LeDoux JE: Emotion, memory and the brain. Sci Am 1994, 270:50-7.
• [37]Lisman J, Schulman H, Cline H: The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci 2002, 3:175-90.
• [38]Liu SB, Zhao R, Li XS, Guo HJ, Tian Z, Zhang N, et al.: Attenuation of reserpine-induced pain/depression dyad by gentiopicroside through downregulation of GluN2B receptors in the amygdala of mice. Neuromolecular Med 2014, 16:350-9.
• [39]Guo YY, Liu SB, Cui GB, Ma L, Feng B, Xing JH, et al.: Acute stress induces down-regulation of large-conductance Ca2 + −activated potassium channels in the lateral amygdala. J Physiol 2012, 590:875-86.