Effect of Reboxetine Treatment on BDNF, Synaptophysin, and PSD-95 Levels in the Spinal Dorsal Horn of Rats with Diabetic Neuropathy

Year 2023, , 710 - 718, 29.12.2023

Nazlı Turan Yücel , Umut İrfan Üçel , Ümide Demir Özkay , Emel Ulupınar , Özgür Devrim Can

https://doi.org/10.33808/clinexphealthsci.1222028

Abstract

Objective: It is known that neuropathic pain is accompanied by alterations in the levels of neurotrophic factors and synaptic proteins in the microenvironment of the spinal dorsal horn. Such changes contribute to hyperalgesia and allodynia processes; thus, analgesic drugs can exert their pharmacological effects by affecting the expressions, levels, or functions of these endogenous substances. In this study, based on the knowledge that reboxetine (a selective noradrenaline reuptake inhibitor) has the potential for antihyperalgesic efficacy in diabetic neuropathy, we aimed to examine the probable effects of this drug on diabetes-induced changes in brain-derived neurotrophic factor (BDNF), synaptophysin (the pre-synaptic marker of synaptic integration), and postsynaptic density-95 (PSD-95) (the postsynaptic marker of synaptic integration) levels in the superficial laminae of the dorsal horn.
Methods: Experimental diabetes was induced by a single-dose injection of streptozotocin (STZ) (50 mg/kg) in rats. After four week-long induction period of painful diabetic neuropathy, rats were treated orally with 8 mg/kg reboxetine for two weeks. Hyperalgesia responses were evaluated by using the Randall–Selitto and Hargreave's tests. Following the pain tests, immunohistochemical studies were performed.
Results: Two weeks of reboxetine administration increased the reduced paw withdrawal thresholds and shortened the paw withdrawal latencies of diabetic rats in neuropathic pain tests, indicating the antihyperalgesic efficacy of this drug. Moreover, augmented BDNF and synaptophysin levels in diabetic rats reversed by reboxetine treatment. However, there was no alteration in the densities of PSD-95, in both STZ-diabetic and reboxetine-treated STZ-diabetic rats.
Conclusion: The obtained results suggested that inhibition of central sensitization and modulation of spinal plasticity seem to be pharmacological mechanisms underlying reboxetine's antihyperalgesic effects on diabetic rats. However, further studies are still needed to clarify the exact mechanism of action.

Keywords

Brain-derived neurotrophic factor, diabetes mellitus, neuropathic pain, postsynaptic density-95, synaptophysin.

Supporting Institution

This work was financially supported by the Anadolu University Research Projects Commission

Project Number

Project No. 1105S084

References

• Siniscalco D, Giordano C, Rossi F, Maione S, de Novellis V. Role of neurotrophins in neuropathic pain. Curr Neuropharmacol. 2011;9:523-529. DOI:10.2174/157015911798376208
• Singh R, Kishore L, Kaur N. Diabetic peripheral neuropathy: Current perspective and future directions. Pharmacol Res. 2014;80:21-35. DOI:10.1016/j.phrs.2013.12.005
• Hernández Reyes JE, Salinas Abarca AB, Vidal Cantú GC, Raya Tafolla G, Elias Viñas D, Granados Soto V, Delgado Lezama R. α5GABAA receptors play a pronociceptive role and avoid the rate-dependent depression of the Hoffmann reflex in diabetic neuropathic pain and reduce primary afferent excitability. Pain 2019;160(6):1448-1458. DOI:10.1097/j.pain.0000000000001515
• Lanlua P, Prommahom A, Sricharoenvej S. Increased number of activated microglia in rat spinal cord during early stage of diabetic induction. Folia Morphol (Warsz) 2020;79(4):662-671. DOI:10.5603/FM.a2019.0136
• Didangelos T, Doupis J, Veves A. Painful diabetic neuropathy: Clinical aspects. Handb Clin Neurol. 2014;126:53-61. DOI:10.1016/B978-0-444-53480-4.00005-9
• Schreiber AK, Nones CFM, Reis RC, Chichorro JG, Cunha JM. Diabetic neuropathic pain: Physiopathology and treatment. World J Diabetes 2015;6(3):432-444. DOI:10.4239/wjd.v6.i3.432
• Sah DWY, Ossipo MH, Porreca F. Neurotrophic factors as novel therapeutics for neuropathic pain. Nat Rev Drug Discov. 2003;2(6):460-472. DOI:10.1038/nrd1107
• Pezet S, McMahon SB. Neurotrophins: Mediators and modulators of pain. Annu Rev Neurosci. 2006;29:507-538. DOI:10.1146/annurev.neuro.29.051605.112929
• Nijs J, Meeus M, Versijpt J, Moens M, Bos I, Knaepen K, Meeusen R. Brain-derived neurotrophic factor as a driving force behind neuroplasticity in neuropathic and central sensitization pain: A new therapeutic target? Expert Opin Ther Targets 2015;19:565-576. DOI:10.1517/14728222.2014.994506
• Khan N, Smith MT. Neurotrophins and neuropathic pain: role in pathobiology. Molecules 2015;20:10657-10688. DOI:10.3390/molecules200610657
• Kuner R. Central mechanisms of pathological pain. Nat Med. 2010;16:1258–1266. DOI: 10.1038/nm.2231
• Luo C, Kuner T, Kuner R. Synaptic plasticity in pathological pain. Trends Neurosci 2014;37:343-355. DOI:10.1016/j.tins.2014.04.002
• Wang R, Qiu Z, Wang G, Hu Q, Shi N, Zhang Z, Wu Y, Zhou C. Quercetin attenuates diabetic neuropathic pain by inhibiting mTOR/p70S6K pathway-mediated changes of synaptic morphology and synaptic protein levels in spinal dorsal horn of db/db mice. Eur J Pharmacol. 2020;882:173266. DOI:10.1016/j.ejphar.2020.173266
• Zhang Z, Ding X, Zhou Z, Qiu Z, Shi N, Zhou S, Du L, Zhu X, Wu Y, Yin X, Zhou C. Sirtuin 1 alleviates diabetic neuropathic pain by regulating synaptic plasticity of spinal dorsal horn neurons. Pain 2019;160:1082-1092. DOI:10.1097/j.pain.0000000000001489
• Preskorn SH. Reboxetine: a norepinephrine selective reuptake pump inhibitor. J Psychiatr Pract 2004;10(1):57-63. DOI:10.1097/00131746-200401000-00006
• Schüler P, Seibel K, Chevts V, Schaffler K. Analgetische wirkung des selektiven noradrenalinwiederaufnahme-hemmers reboxetin. Der Nervenarzt. 2002;73(2):149-154 (German). DOI:10.1007/s00115-001-1226-7
• Schreiber S, Frishtick R, Volis I, Rubovitch V, Pick CG, Weizman R. The antinociceptive properties of reboxetine in acute pain. Eur Neuropsychopharmacol. 2009;19(10):735-739. DOI:10.1016/j.euroneuro.2009.06.004
• Hughes S, Hickey L, Donaldson LF, Lumb BM, Pickering AE. Intrathecal reboxetine suppresses evoked and ongoing neuropathic pain behaviours by restoring spinal noradrenergic inhibitory tone. Pain 2015;156(2):328-334. DOI:10.1097/01.j.pain.0000460313.73358.31
• Turan Yücel N, Can ÖD, Demir Özkay Ü. Catecholaminergic and opioidergic system mediated effects of reboxetine on diabetic neuropathic pain. Psychopharmacology 2020;237(4):1131-1145. DOI:10.1007/s00213-019-05443-5
• Üçel Uİ, Can ÖD, Demir Özkay Ü, Öztürk Y. Antihyperalgesic and antiallodynic effects of mianserin on diabetic neuropathic pain: A study on mechanism of action. Eur J Pharmacol. 2015;756:92-106. DOI:10.1016/j.ejphar.2015.02.048
• Cho HJ, Kim JK, Zhou XF, Rush RA. Increased brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia and spinal cord following peripheral inflammation. Brain Res. 1997;764(1-2):269-272. DOI:10.1016/s0006-8993(97)00597-0
• Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Ann Rev Neurosci. 2001;24:677-736. DOI:10.1146/annurev.neuro.24.1.677
• Bathina S, Das UN. Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci. 2015;11(6):1164-1178. DOI:10.5114/aoms.2015.56342
• Beggs S, Salter MW. Microglia–neuronal signaling in neuropathic pain hypersensitivity 2.0. Curr Opin Neurobiol. 2010;20(4):474-480. DOI:10.1016/j.conb.2010.08.005
• Wen YR, Tan PH, Cheng JK, Liu YC, Ji RR. Microglia: a promising target for treating neuropathic and postoperative pain, and morphine tolerance. J Formos Med Assoc. 2011;110(8):487-494. DOI:10.1016/S0929-6646(11)60074-0
• Obata K, Noguchi K. BDNF in sensory neurons and chronic pain. Neurosci Res. 2006;55(1):1-10. DOI:10.1016/j.neures.2006.01.005
• Sikandar S, Minett MS, Millet Q, Santana-Varela S, Lau J, Wood JN, Zhao J. Brain-derived neurotrophic factor derived from sensory neurons plays a critical role in chronic pain. Brain 2018;141(4):1028-1039. DOI:10.1093/brain/awy009
• Ismail CAN, Suppian R, Ab Aziz CB, Long I. Expressions of spinal microglia activation, BDNF, and DREAM proteins correlated with formalin-induced nociceptive responses in painful and painless diabetic neuropathy rats. Neuropeptides 2020;79:102003. DOI:10.1016/j.npep.2019.102003
• Smith PA. BDNF: No gain without pain? Neurosci. 2014;283:107-123. DOI:10.1016/j.neuroscience.2014.05.044
• Chen JT, Guo D, Campanelli D, Frattini F, Mayer F, Zhou L, Kuner R, Heppenstall PA, Knipper M, Hu J. Presynaptic GABAergic inhibition regulated by BDNF contributes to neuropathic pain induction. Nat Commun. 2014;5:5331. DOI:10.1038/ncomms6331
• Geng SJ, Liao FF, Dang WH, Ding X, Liu XD, Cai J, Han JS, Wan Y, Xing GG. Contribution of the spinal cord BDNF to the development of neuropathic pain by activation of the NR2B-containing NMDA receptors in rats with spinal nerve ligation. Exp Neurol. 2010;222(2):256-266. DOI:10.1016/j.expneurol.2010.01.003
• Ciobanu C, Reid G, Babes A. Acute and chronic effects of neurotrophic factors BDNF and GDNF on responses mediated by thermo-sensitive TRP channels in cultured rat dorsal root ganglion neurons. Brain Res. 2009;1284:54-67. DOI:10.1016/j.brainres.2009.06.014
• Zhang X, Xu Y, Wang J, Zhou Q, Pu S, Jiang W, Du D. The effect of intrathecal administration of glial activation inhibitors on dorsal horn BDNF overexpression and hind paw mechanical allodynia in spinal nerve ligated rats. J Neural Transm. 2012;119(3):329-336. DOI:10.1007/s00702-011-0713-7
• Vanelderen P, Rouwette T, Kozicz T, Heylen R, Van Zundert J, Roubos EW, Vissers K. Effects of chronic administration of amitriptyline, gabapentin and minocycline on spinal brain-derived neurotrophic factor expression and neuropathic pain behavior in a rat chronic constriction injury model. Reg Anesth Pain Med. 2013;38(2):124-130. DOI:10.1097/AAP.0b013e31827d611b
• Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter WS, De Koninck Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005;438(7070):1017-1021. DOI:10.1038/nature04223
• Miletic G, Miletic V. Increases in the concentration of brain derived neurotrophic factor in the lumbar spinal dorsal horn are associated with pain behavior following chronic constriction injury in rats. Neurosci Letters 2002;319(3):137-140. DOI:10.1016/s0304-3940(01)02576-9
• Biggs JE, Lu VB, Stebbing MJ, Balasubramanyan S, Smith PA. Is BDNF sufficient for information transfer between microglia and dorsal horn neurons during the onset of central sensitization? Mol Pain. 2010;6:44. DOI:10.1186/1744-8069-6-44
• Ge H, Guan S, Shen Y, Sun M, Hao Y, He L, Liu L, Yin C, Huang R, Xiong W, Gao Y. Dihydromyricetin affects BDNF levels in the nervous system in rats with comorbid diabetic neuropathic pain and depression. Sci Rep. 2019;9(1):14619. DOI:10.1038/s41598-019-51124-w
• Chen M, Tian YK, Xiang HB. Synaptophysin and neuropathic pain. Acad J Second Mil Med Univ. 2006;27(10):1142-1144.
• Jaken RJ, Joosten EA, Knüwer M, Miller R, van der Meulen I, Marcus MA, Deumens R. Synaptic plasticity in the substantia gelatinosa in a model of chronic neuropathic pain. Neurosci Lett. 2010;469(1):30-33. DOI:10.1016/j.neulet.2009.11.038
• Ikeda H, Kiritoshi T, Murase K. Synaptic plasticity in the spinal dorsal horn. Neurosci Res. 2009;64(2):133-136. DOI:10.1016/j.neures.2009.03.004
• Atasoy D, Kavalali ET. Presynaptic development: Functional and morphological organization. Squire LR, editor. Encyclopedia of Neuroscience. Spain: Academic Press-Elsevier Ltd.; 2009.p.967-974. DOI:10.1016/B978-008045046-9.01772-1
• Zhou K, Wu Q, Yue J, Yu X, Ying X, Chen X, Zhou Y, Yang G, Tu W, Jiang S. Electroacupuncture suppresses spinal nerve ligation-induced neuropathic pain via regulation of synaptic plasticity through upregulation of basic fibroblast growth factor expression. Acupunct Med. 2022;40(4):379-388. DOI:10.1177/09645284211066499
• Gordon SL, Harper CB, Smillie KJ, Cousin MA. A fine balance of synaptophysin levels underlies efficient retrieval of synaptobrevin II to synaptic vesicles. PLoS One 2016;11(2):e0149457. DOI:10.1371/journal.pone.0149457
• Wiedenmann B. Synaptophysin. A widespread constituent of small neuroendocrine vesicles and a new tool in tumor diagnosis. Acta Oncol. (Stockholm, Sweden) 1991;30(4):435 440. DOI:10.3109/02841869109092398
• d'Mello R, Marchand F, Pezet S, McMahon SB, Dickenson AH. Perturbing PSD-95 interactions with NR2B-subtype receptors attenuates spinal nociceptive plasticity and neuropathic pain. Mol Ther. 2011;19(10):1780-1792. DOI:10.1038/mt.2011.42
• Stratton HJ, Khanna R. Sculpting dendritic spines during initiation and maintenance of neuropathic pain. J Neurosci. 2020;40(40):7578-7589. DOI:10.1523/JNEUROSCI.1664-20.2020
• Chen X, Nelson CD, Li X, Winters CA, Azzam R, Sousa AA, Leapman DR, Gainer H, Sheng M, Reese TS. PSD-95 is required to sustain the molecular organization of the postsynaptic density. J Neurosci. 2011;31(17):6329-6338. DOI:10.1523/JNEUROSCI.5968-10.2011
• Yoo KS, Lee K, Oh JY, Lee H, Park H, Park YS, Kim HK. Postsynaptic density protein 95 (PSD-95) is transported by KIF5 to dendritic regions. Mol Brain 2019;12(1):1-12. DOI:10.1186/s13041-019-0520-x
• Calabrese D, Giatti S, Romano S, Porretta-Serapiglia C, Bianchi R, Milanese M, Bonanno G, Caruso D, Viviani B, Gardoni F, Garcia-Segura LM, Melcangi RC. Diabetic neuropathic pain: a role for testosterone metabolites. J Endocrinol. 2014;221(1):1-13. DOI:10.1530/JOE-13-0541
• Muñoz-Cobo I, Erburu MM, Zwergel C, Cirilli R, Mai A, Valente S, Puerta E, Tordera RM. Nucleocytoplasmic export of HDAC5 and SIRT2 downregulation: two epigenetic mechanisms by which antidepressants enhance synaptic plasticity markers. Psychopharmacology 2018;235(10):2831-2846. DOI:10.1007/s00213-018-4975-8
• Russo-Neustadt AA, Alejandre H, Garcia C, Ivy AS, Chen MJ. Hippocampal brain-derived neurotrophic factor expression following treatment with reboxetine, citalopram, and physical exercise. Neuropsychopharmacology 2004;29(12):2189-2199. DOI:10.1038/sj.npp.1300514
• Gao S, Zhang X, Xu H, Miao D, Qian J, Wu Z, Shi W. Promoting the hippocampal PPARα expression participates in the antidepressant mechanism of reboxetine, a selective norepinephrine reuptake inhibitor. Behav Brain Res. 2022;416:113535. DOI:10.1016/j.bbr.2021.113535
• Młyniec K, Nowak G. Up-regulation of the GPR39 Zn2+-sensing receptor and CREB/BDNF/TrkB pathway after chronic but not acute antidepressant treatment in the frontal cortex of zinc-deficient mice. Pharmacol Rep. 2015;67(6):1135-1140. DOI:10.1016/j.pharep.2015.04.003
• First M, Gil-Ad I, Taler M, Tarasenko I, Novak N, Weizman A. The effects of reboxetine treatment on depression-like behavior, brain neurotrophins, and ERK expression in rats exposed to chronic mild stress. J Mol Neurosci. 2013;50(1):88-97. DOI:10.1007/s12031-012-9872-8