题名

Inhibition of Neuropathic Pain by a Single Intraperitoneal Injection of Diazepam in the Rat: Possible Role of Neurosteroids

DOI

10.4077/CJP.2016.BAD332

作者

Shu-Ling Chen；Ying Zang；Wen-Hui Zheng；Xu-Hong Wei；Xian-Guo Liu

关键词

diazepam ； interleukin ； neuropathic pain ； pregnenolone ； spinal cord ； TSPO

期刊名称

The Chinese Journal of Physiology

卷期/出版年月

59卷1期（2016 / 02 / 29）

页次

9 - 20

内容语文

英文
英文摘要

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.
主题分类 醫藥衛生 > 基礎醫學
参考文献
  1. Bao, L.,Zhu, Y.,Elhassan, A.M.,Wu. Q.,Xiao, B.,Zhu, J.,Lindgren, J.U.(2001).Adjuvant-induced arthritis: IL-1 beta, IL-6 and TNF-alpha are up-regulated in the spinal cord.Neuroreport,12,3905-3908.
  2. Basbaum, A.I.(1999).Distinct neurochemical features of acute and persistent pain.Proc. Natl. Acad. Sci. USA,96,7739-7743.
  3. Baulieu, E.E.,Robel, P.,Schumacher, M.(2001).Neurosteroids: beginning of the story.Int. Rev. Neurobiol.,46,1-32.
  4. Callachan, H.,Cottrell, G.A.,Hather, N.Y.,Lambert, J.J.,Nooney, J.M.,Peters, J.A.(1987).Modulation of the GABAA receptor by progesterone metabolites.Proc. R. Soc. Lond. B. Biol. Sci.,231,359-369.
  5. Chaplan, S.R.,Bach, F.W.,Pogrel, J.W.,Chung, J.M.,Yaksh, T.L.(1994).Quantitative assessment of tactile allodynia in the rat paw.J. Neurosci. Methods,53,55-63.
  6. Coronel, M.F.,Labombarda, F.,Roig, P.,Villar, M.J.,De Nicola, A.F.,González, S.L.(2011).Progesterone prevents nerve injury-induced allodynia and spinal NMDA receptor upregulation in rats.Pain Med.,12,1249-1261.
  7. DeLeo, J.A.,Colburn, R.W.,Rickman, A.J.(1997).Cytokine and growth factor immunohistochemical spinal profiles in two animal models of mononeuropathy.Brain Res.,759,50-57.
  8. Do-Rego, J.L.,Mensah-Nyagan, A.G.,Beaujean, D.,Leprince, J.,Tonon, M.C.,Luu-The, V.,Pelletier, G.,Vaudry, H.(2001).The octadecaneuropeptide ODN stimulates neurosteroid biosynthesis through activation of central-type benzodiazepine receptors.J. Neurochem,76,128-138.
  9. Garnier, M.,Boujrad, N.,Oke, B.O.,Brown, S.,Riond, J.,Ferrara, P.,Shoyab, M.,Suarez-Quian, A.,Papadopoulos, V.(1993).Diazepam binding inhibitor is a paracrine/autocrine regulator of Leydig cell proliferation and steroidogenesis: action via peripheral-type benzodiazepine receptor and independent mechanisms.Endocrinology,132,444-458.
  10. Gwak, Y.S.,Tan, H.Y.,Nam. T.S.,Paik, K.S.,Hulsebosch, C.E.,Leem, J.W.(2006).Activation of spinal GABA receptors attenuates chronic central neuropathic pain after spinal cord injury.J. Neurotrauma,23,1111-1124.
  11. Hargreaves, K.,Dubner, R.,Brown. F.,Flores, C.,Joris, J.(1988).A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.Pain,32,77-88.
  12. Hu, X.D.,Ge, Y.X.,Hu, N.W.,Zhang, H.M.,Zhou, L.J.,Zhang, T.,Li, W.M.,Han, Y.F.,Liu, X.G.(2006).Diazepam inhibits the induction and maintenance of LTP of C-fiber evoked field potentials in spinal dorsal horn of rats.Neuropharmacology,50,238-244.
  13. Ji, R.R.,Kohno, T.,Moore, K.A.,Woolf, C.J.(2003).Central sensitization and LTP: do pain and memory share similar mechanisms?.Trends Neurosci.,26,696-705.
  14. Jiang, C.,Cui, K.,Wang, J.,He, Y.(2011).Microglia and cyclooxygenase-2: possible therapeutic targets of progesterone for stroke.Int. Immunopharmacol.,11,1925-1931.
  15. Kancheva, R.,Hill, M.,Novak, Z.,Chrastina, J.,Kancheva, L.,Stárka, L.(2011).Neuroactive steroids in periphery and cerebrospinal fluid.Neuroscience,191,22-27.
  16. Kaur, P.,Kim, K.(2008).Pharmacokinetics and brain uptake of diazepam after intravenous and intranasal administration in rats and rabbits.Int. J. Pharm.,364,27-35.
  17. Kawasaki, Y.,Zhang, L.,Cheng, J.K.,Ji, R.R.(2008).Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord.J. Neurosci.,28,5189-5194.
  18. Kim, S.H.,Chung, J.M.(1992).An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat.Pain,50,355-363.
  19. Knabl, J.,Witschi, R.,Hösl, K.,Reinold, H.,Zeilhofer, U.B.,Ahmadi, S.,Brockhaus, J.,Sergejeva, M.,Hess, A.,Brune, K.,Fritschy, J.M.,Rudolph, U.,Möhler, H.,Zeilhofer, H.U.(2008).Nature,451,330-334.
  20. Lacor, P.,Benavides, J.,Ferzaz, B.(1996).Enhanced expression of the peripheral benzodiazepine receptor (PBR) and its endogenous ligand octadecaneuropeptide (ODN) in the regenerating adult rat sciatic nerve.Neurosci. Lett.,220,61-65.
  21. Lazzarini, R.,Malucelli, B.E.,Muscará, M.N.,de Nucci, G.,Palermo-Neto, J.(2003).Reduction of inflammation in rats by diazepam: tolerance development.Life Sci.,72,2361-2368.
  22. Lazzarini, R.,Malucelli, B.E.,Palermo-Neto, J.(2001).Reduction of acute inflammation in rats by diazepam: role of peripheral benzodiazepine receptors and corticosterone.Immunopharmacol. Immunotoxicol.,23,253-265.
  23. Loggia, M.L.,Chonde, D.B.,Akeju, O.,Arabasz, G.,Catana, C.,Edwards, R.R.,Hill, E.,Hsu, S.,Izquierdo-Garcia, D.,Ji, R.R.,Riley, M.,Wasan, A.D.,Zurcher, N.R.,Albrecht, D.S.,Vangel, M.G.,Rosen, B.R.,Napadow, V.,Hooker, J.M.(2015).Evidence for brain glial activation in chronic pain patients.Brain,138,604-615.
  24. Mellon, S.H.(2007).Neurosteroid regulation of central nervous system development.Pharmacol. Ther.,116,107-124.
  25. Mensah-Nyagan, A.G.,Meyer, L.,Schaeffer, V.,Kibaly, C.,Patte-Mensah, C.(2009).Evidence for a key role of steroids in the modulation of pain.Psychoneuroendocrinology,34(Suppl 1),S169-S177.
  26. Meyer, L.,Patte-Mensah, C.,Taleb, O.,Mensah-Nyagan, A.G.(2011).Allopregnanolone prevents and suppresses oxaliplatin-evoked painful neuropathy: multi-parametric assessment and direct evidence.Pain,152,170-181.
  27. Mitchell, E.A.,Gentet, L.J.,Dempster, J.,Belelli, D.(2007).GABAA and glycine receptor-mediated transmission in rat lamina II neurons: relevance to the analgesic actions of neuroactive steroids.J. Physiol.,583,1021-1040.
  28. Mitchell, E.A.,Herd, M.B.,Gunn, B.G.,Lambert, J.J.,Belelli, D.(2008).Neurosteroid modulation of GABAA receptors: molecular determinants and significance in health and disease.Neurochem. Int.,52,588-595.
  29. Nothdurfter, C.,Baghai, T.C.,Schule, C.,Rupprecht, R.(2012).Translocator protein (18 kDa) (TSPO) as a therapeutic target for anxiety and neurologic disorders.Eur. Arch. Psychiatry Clin. Neurosci.,262(Suppl 2),S107-S112.
  30. Olsen, R.W.,McCabe, R.T.,Wamsley, J.K.(1990).GABAA receptor subtypes: autoradiographic comparison of GABA, benzodiazepine, and convulsant binding sites in the rat central nervous system.J. Chem. Neuroanat.,3,59-76.
  31. Papadopoulos, V.,Baraldi, M.,Guilarte, T.R.,Knudsen, T.B.,Lacapere, J.J.,Lindemann, P.,Norenberg, M.D.,Nutt, D.,Weizman, A.,Zhang, M.R.,Gavish, M.(2006).Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function.Trends Pharmacol. Sci.,27,402-409.
  32. Papadopoulos, V.,Mukhin, A.G.,Costa, E.,Krueger, K.E.(1990).The peripheral-type benzodiazepine receptor is functionally linked to Leydig cell steroidogenesis.J. Biol. Chem.,265,3772-3779.
  33. Pathirathna, S.,Brimelow, B.C.,Jagodic, M.M.,Krishnan, K.,Jiang, X.,Zorumski, C.F.,Mennerick, S.,Covey, D.F.,Todorovic, S.M.,Jevtovic-Todorovic, V.(2005).New evidence that both T-type calcium channels and GABAA channels are responsible for the potent peripheral analgesic effects of 5alpha-reduced neuroactive steroids.Pain,114,429-443.
  34. Pathirathna, S.,Todorovic, S.M.,Covey, D.F.,Jevtovic-Todorovic, V.(2005).5alpha-reduced neuroactive steroids alleviate thermal and mechanical hyperalgesia in rats with neuropathic pain.Pain,117,326-339.
  35. Ramseier, H.,Lichtensteiger, W.,Schlumpf, M.(1993).In vitro inhibition of cellular immune responses by benzodiazepines and PK 11195. Effects on mitogen- and alloantigen-driven lymphocyte proliferation and on IL-1, IL-2 synthesis and IL-2 receptor expression.Immunopharmacol. Immunotoxicol.,15,557-582.
  36. Romero-Sandoval, A.,Chai, N.,Nutile-McMenemy, N.,Deleo, J.A.(2008).A comparison of spinal Iba1 and GFAP expression in rodent models of acute and chronic pain.Brain Res.,1219,116-126.
  37. Rupprecht, R.,Papadopoulos, V.,Rammes, G.,Baghai, T.C.,Fan, J.,Akula, N.,Groyer, G.,Adams, D.,Schumacher, M.(2010).Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders.Nat. Rev. Drug Discov.,9,971-988.
  38. Sandkuhler, J.(2007).Understanding LTP in pain pathways.Mol. Pain,3,9.
  39. Smith, H.S.(2010).Activated microglia in nociception.Pain Physician,13,295-304.
  40. Snyder, S.H.,Verma, A.,Trifiletti, R.R.(1987).The peripheral-type benzodiazepine receptor: a protein of mitochondrial outer membranes utilizing porphyrins as endogenous ligands.FASEB J.,1,282-288.
  41. Watkins, L.R.,Maier, S.F.(2003).Glia: a novel drug discovery target for clinical pain.Nat. Rev. Drug Discov.,2,973-985.
  42. Wei, X.H.,Na, X.D.,Liao, G.J.,Chen, Q.Y.,Cui, Y.,Chen, F.Y.,Li, Y.Y.,Zang, Y.,Liu, X.G.(2013).The up-regulation of IL-6 in DRG and spinal dorsal horn contributes to neuropathic pain following L5 ventral root transection.Exp. Neurol.,241,159-168.
  43. Wei, X.H.,Wei, X.,Chen, F.Y.,Zang, Y.,Xin, W.J.,Pang, R.P.,Chen, Y.,Wang, J.,Li, Y.Y.,Shen, K.F.,Zhou, L.J.,Liu, X.G.(2013).The upregulation of translocator protein (18 kDa) promotes recovery from neuropathic pain in rats.J. Neurosci.,33,1540-1551.
  44. Wei, X.H.,Yang, T.,Wu, Q.,Xin, W.J.,Wu, J.L.,Wang, Y.Q.,Zang, Y.,Wang, J.,Li, Y.Y.,Liu, X.G.(2012).Peri-sciatic adminis tration of recombinant rat IL-1beta induces mechanical allodynia by activation of src-family kinases in spinal microglia in rats.Exp. Neurol.,234,389-397.
  45. Wei, X.H.,Zang, Y.,Wu, C.Y.,Xu, J.T.,Xin, W.J.,Liu, X.G.(2007).Peri-sciatic administration of recombinant rat TNF-alpha induces mechanical allodynia via upregulation of TNF-alpha in dorsal root ganglia and in spinal dorsal horn: the role of NF-kappa B pathway.Exp. Neurol.,205,471-484.
  46. Weir, C.J.,Ling, A.T.,Belelli, D.,Wildsmith, J.A.,Peters, J.A.,Lambert, J.J.(2004).The interaction of anaesthetic steroids with recombinant glycine and GABAA receptors.Brit. J. Anaesth.,92,704-711.
  47. Wilms, H.,Claasen, J.,Rohl, C.,Sievers, J.,Deuschl, G.,Lucius, R.(2003).Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases: evidence from activated microglial cells in vitro.Neurobiol. Dis.,14,417-424.
  48. Woolf, C.J.,Mannion, R.J.(1999).Neuropathic pain: aetiology, symptoms, mechanisms, and management.Lancet,353,1959-1964.
  49. Woolf, C.J.,Salter, M.W.(2000).Neuronal plasticity: increasing the gain in pain.Science,288,1765-1769.
  50. Xu, J.T.,Xin, W.J.,Zang, Y.,Wu, C.Y.,Liu, X.G.(2006).The role of tumor necrosis factor-alpha in the neuropathic pain induced by Lumbar 5 ventral root transection in rat.Pain,123,306-321.
  51. Young, W.S.III.,Kuhar, M.J.(1980).Radiohistochemical localization of benzodiazepine receptors in rat brain.J. Pharmacol. Exp. Ther.,212,337-346.
  52. Zavala, F.(1997).Benzodiazepines, anxiety and immunity.Pharmacol. Ther.,75,199-216.
  53. Zimmermann, M.(1983).Ethical guidelines for investigations of experimental pain in conscious animals.Pain,16,109-110.
print cancel