Volume 24, Issue 5 (9-2020)                   IBJ 2020, 24(5): 306-313 | Back to browse issues page

PMID: 32429644

XML Print

Background: Neuropathic pain, due to peripheral nerve damage, has influenced millions of people living all over the world. It has been shown that paroxetine can relieve neuropathic pain. Recently, the role of certain proteins like brain-derived neurotrophic factor (BDNF), GABAA receptor, and K+-Cl- cotransporter 2 (KCC2) transporter in the occurrence of neuropathic pain has been documented. In the current study, the expression of these proteins affected by paroxetine was evaluated. Methods: Male Wistar rats were allocated into two main groups of pre- and post-injury. Rats in each main group received paroxetine before nerve injury and at day seven after nerve damage till day 14, respectively. The lumbar spinal cord of animals was extracted to assess the expression of target genes and proteins. Results: In the preventive study, paroxetine decreased BDNF and increased KCC2 and GABAA gene and protein expression, while in the post-injury paradigm, it decreased BDNF and increased KCC2 genes and protein expression. In this regard, an increase in the protein expression of GABAA was observed. Conclusion: It seems that paroxetine with a change in the expression of three significant proteins involved in neuropathic pain could attenuate this type of chronic pain.
Type of Study: Full Length/Original Article | Subject: Related Fields

1. Backonja MM, Stacey B. Neuropathic pain symptoms relative to overall pain rating. The journal of pain 2004; 5(9): 491-497. [DOI:10.1016/j.jpain.2004.09.001]
2. Hald A, Nedergaard S, Hansen RR, Ding M, Heegaard AM. Differential activation of spinal cord glial cells in murine models of neuropathic and cancer pain. European journal of pain 2009; 13(2): 138-145. [DOI:10.1016/j.ejpain.2008.03.014]
3. Hald A. Spinal astrogliosis in pain models: cause and effects. Cellular and molecular neurobiology 2009; 29(5): 609-619. [DOI:10.1007/s10571-009-9390-6]
4. Kemler MA, de Vet HC, Barendse GA, van den Wildenberg FA, van Kleef M. Effect of spinal cord stimulation for chronic complex regional pain syndrome Type I: five-year final follow-up of patients in a randomized controlled trial. Journal of neurosergery 2008; 108(2): 292-298. [DOI:10.3171/JNS/2008/108/2/0292]
5. Bowery NG, Hudson AL, Price GW. GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 1987; 20(2): 365-383. [DOI:10.1016/0306-4522(87)90098-4]
6. Price TJ, Cervero F, de Koninck Y. Role of cation-chloride-cotransporters (CCC) in pain and hyperalgesia. Current topics in medicinal chemistry 2005; 5(6): 547-555. [DOI:10.2174/1568026054367629]
7. Vinay L, Jean-Xavier C. Plasticity of spinal cord locomotor networks and contribution of cation-chloride cotransporters. Brain research reviews 2008; 57(1): 103-110. [DOI:10.1016/j.brainresrev.2007.09.003]
8. Cramer SW, Baggott C, Cain J, Tilghman J, Allcock B, Miranpuri G, Rajpal S, Sun D, Resnick D. The role of cation-dependent chloride transporters in neuropathic pain following spinal cord injury. Molecular pain 2008; 4(1): 36. [DOI:10.1186/1744-8069-4-36]
9. Eaton MJ, Wolfe SQ, Martinez M, Hernandez M, Furst C, Huang J, Frydel BR, Gómez-Marín O. Subarachnoid transplant of a human neuronal cell line attenuates chronic allodynia and hyperalgesia after excitotoxic spinal cord injury in the rat. The journal of pain 2007; 8(1): 33-50. [DOI:10.1016/j.jpain.2006.05.013]
10. Miletic G, Draganic P, Pankratz MT, Miletic V. Muscimol prevents long-lasting potentiation of dorsal horn field potentials in rats with chronic constriction injury exhibiting decreased levels of the GABA transporter GAT-1. Pain 2003; 105(1): 347-353. [DOI:10.1016/S0304-3959(03)00250-1]
11. Alvarez-Leefmans FJ, Leon-Olea M, Mendoza-Sotelo J, Alvarez FJ, Anton B, Garduno R. Immunolocalization of the Na+-K+-2Cl- cotransporter in peripheral nervous tissue of vertebrates. Neuroscience 2001; 104(2): 569-582 . [DOI:10.1016/S0306-4522(01)00091-4]
12. Misgeld U, Deisz RA, Dodt HU, Lux HD. The role of chloride transport in postsynaptic inhibition of hippocampal neurons. Science 1986; 232: 1413-1415. [DOI:10.1126/science.2424084]
13. Sung KW, Kirby M, McDonald MP, Lovinger DM, Delpire E. Abnormal GABAA receptor-mediated currents in dorsal root ganglion neurons isolated from Na-K-2Cl cotransporter null mice. Journal neurosci 2000; 20(20): 7531-7538. [DOI:10.1523/JNEUROSCI.20-20-07531.2000]
14. Miletic G, Miletic V. Loose ligation of the sciatic nerve is associated with TrkB receptor-dependent decreases in KCC2 protein levels in the ipsilateral spinal dorsal horn. Pain 2008; 137(3): 532-539. [DOI:10.1016/j.pain.2007.10.016]
15. DeLeo JA, Yezierski RP. The role of neuro-inflammation and neuroimmune activation in persistent pain. Pain 2001; 90(1-2): 1-6. [DOI:10.1016/S0304-3959(00)00490-5]
16. Garrison C, Dougherty P, Kajander K, Carlton S. Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain research 1991; 565(1): 1-7. [DOI:10.1016/0006-8993(91)91729-K]
17. DeLeo JA, Colburn RW. Proinflammatory cytokines and glial cells: their role in neuropathic pain. Cytokines and pain 1999: 159-181. [DOI:10.1007/978-3-0348-8749-6_7]
18. Zhuang ZY, Kawasaki Y, Tan PH, Wen YR, Huang J, Ji R-R. Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain, behavior, and immunity 2007; 21(5): 642-651. [DOI:10.1016/j.bbi.2006.11.003]
19. Trang T, Beggs S, Wan X, Salter MW. P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. Journal neurosci 2009; 29(11): 3518-3528. [DOI:10.1523/JNEUROSCI.5714-08.2009]
20. Merighi A, Salio C, Ghirri A, Lossi L, Ferrini F, Betelli C, Bardoni R. BDNF as a pain modulator. Progress in neurobiolgy 2008; 85(3): 297-317 [DOI:10.1016/j.pneurobio.2008.04.004]
21. Obata K, Noguchi K. BDNF in sensory neurons and chronic pain. Journal of neuroscience research 2006; 55(1): 1-10. [DOI:10.1016/j.neures.2006.01.005]
22. Pezet S, McMahon SB. Neurotrophins: mediators and modulators of pain. Annual review of neuroscience 2006; 29: 507-538. [DOI:10.1146/annurev.neuro.29.051605.112929]
23. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, 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]
24. Rivera C, Li H, Thomas-Crusells J, Lahtinen H, Viitanen T, Nanobashvili A, Kokaia Z, Airaksinen MS, Voipio J, Kaila K.Saarma M. BDNF-induced TrkB activation down-regulates the K+-Cl- cotransporter KCC2 and impairs neuronal Cl− extrusion. Journal cell biologyl 2002; 159(5): 747-752. [DOI:10.1083/jcb.200209011]
25. Fukuoka T, Tokunaga A, Kondo E, Miki K, Tachibana T, Noguchi K. Change in mRNAs for neuropeptides and the GABA< sub> A receptor in dorsal root ganglion neurons in a rat experimental neuropathic pain model. Pain 1998; 78(1): 13-26. [DOI:10.1016/S0304-3959(98)00111-0]
26. Inoue K, Tsuda M. Purinergic systems, neuropathic pain and the role of microglia. Experimental neurology 2012; 234(2): 293-301. [DOI:10.1016/j.expneurol.2011.09.016]
27. Wang W, Gu J, Li YQ, Tao YX. Are voltage-gated sodium channels on the dorsal root ganglion involved in the development of neuropathic pain. Molecular pain 2011; 7: 16. [DOI:10.1186/1744-8069-7-16]
28. Toulme E, Garcia A, Samways D, Egan TM, Carson MJ, Khakh BS. P2X4 receptors in activated C8-B4 cells of cerebellar microglial origin. The journal of general physiology 2010; 135(4)333-353. [DOI:10.1085/jgp.200910336]
29. Wall P, Devor M, Inbal R, Scadding J, Schonfeld D, Seltzer Z, Tomkiewicz M. Autotomy following peripheral nerve lesions: experimental anesthesia dolorosa. Pain 1979; 7(2): 103-113. [DOI:10.1016/0304-3959(79)90002-2]
30. Ji RR, Suter MR. p38 MAPK, microglial signaling, and neuropathic pain. Molecular Pain 2007; 3: 33. [DOI:10.1186/1744-8069-3-33]
31. Inoue K, Tsuda M. Microglia and neuropathic pain. Glia 2009; 57(14): 1469-1479. [DOI:10.1002/glia.20871]
32. Imai Y, Ibata I, Ito D, Ohsawa K, Kohsaka S. A novel gene iba1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage. Biochemical and biophysical research communications 1996; 224(3): 855-862. [DOI:10.1006/bbrc.1996.1112]
33. Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S. Microglia-specific localisation of a novel calcium binding protein, Iba1. Molecular brain research 1998; 57(1): 1-9. [DOI:10.1016/S0169-328X(98)00040-0]
34. Ohsawa K, Neo M, Matsuoka H, Akiyama H, Ito H, Kohno H, Nakamura T. The expression of bone matrix protein mRNAs around beta-TCP particles implanted into bone. Journal of biomedical materials research 2000; 52(3): 460-466. https://doi.org/10.1002/1097-4636(20001205)52:3<460::AID-JBM3>3.0.CO;2-U [DOI:10.1002/1097-4636(20001205)52:33.0.CO;2-U]
35. Romero-Sandoval A, Chai N, Nutile-McMenemy N, DeLeo JA. A comparison of spinal Iba1 and GFAP expression in rodent models of acute and chronic pain. Brain research 2008; 1219: 116-126. [DOI:10.1016/j.brainres.2008.05.004]
36. Xiaodi Y, Shuangqiong Z, Qianbo C, Chengwen C, Hongbin Y. P2X4 receptor and brain-derived neurotrophic factor in neuropathic pain. Journal of medical colleges of PLA 2010; 25(5): 275-284. [DOI:10.1016/S1000-1948(11)60013-0]
37. Inoue K, Koizumi S, Tsuda M, Shigemoto-Mogami Y. Signaling of ATP receptors in glia-neuron interaction and pain. Life science 2003; 74(2-3): 189-197. [DOI:10.1016/j.lfs.2003.09.006]
38. Trang T, Salter MW. P2X4 purinoceptor signaling in chronic pain. Purinergic signalling 2012; 8(3): 621-628. [DOI:10.1007/s11302-012-9306-7]
39. North RA. Molecular physiology of P2X receptors. Physiological reviews 2002; 82(4): 1013-1067. [DOI:10.1152/physrev.00015.2002]
40. Geng SJ, Liao F-F, Dang WH, Ding X, Liu XD, Cai J, Han JS, Wan Y, Xing G-G. 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. Experimental neurology 2010; 222(2): 256-266. [DOI:10.1016/j.expneurol.2010.01.003]
41. Hayashida KI, Clayton BA, Johnson JE, Eisenach JC. Brain derived nerve growth factor induces spinal noradrenergic fiber sprouting and enhances clonidine analgesia following nerve injury in rats. Pain 2008; 136(3): 348-355 . [DOI:10.1016/j.pain.2007.07.014]
42. Zarei M, Sabetkasaei M, Zanjani TM. Paroxetine attenuates the development and existing pain in a rat model of neurophatic pain. Iranian biomedical journal 2014; 18(2): 94 -100.
43. Lu Y, Zheng J, Xiong L, Zimmermann M, Yang J. Spinal cord injury-induced attenuation of GABAergic inhibition in spinal dorsal horn circuits is associated with down regulation of the chloride transporter KCC2 in rat. The journal of physiology 2008; 586(23): 5701-5715. [DOI:10.1113/jphysiol.2008.152348]
44. Kaila K. Ionic basis of GABA sub A/sub receptor channel function in the nervous system. Progress in neurobiology 1994; 42(4): 489-537. [DOI:10.1016/0301-0082(94)90049-3]
45. Lu Y, Perl ER. A specific inhibitory pathway between substantia gelatinosa neurons receiving direct C-fiber input. The journal of neuroscience 2003; 23(25): 8752-8758. [DOI:10.1523/JNEUROSCI.23-25-08752.2003]
46. Delpire E. Cation-chloride cotransporters in neuronal communication. Physiology 2000; 15(6): 309-312. [DOI:10.1152/physiologyonline.2000.15.6.309]
47. Payne JA, Rivera C, Voipio J, Kaila K. Cation-chloride co-transporters in neuronal communication, development and trauma. Trends neurosci 2003; 26(4): 199-206. [DOI:10.1016/S0166-2236(03)00068-7]
48. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, DeHoninck Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005; 438(7070): 1017-1021. [DOI:10.1038/nature04223]
49. De Koninck Y. Altered chloride homeostasis in neurological disorders: a new target. Current opinion pharmacol 2007; 7(1): 93-99. [DOI:10.1016/j.coph.2006.11.005]
50. Rudomin P. Presynaptic inhibition of muscle spindle and tendon organ afferents in the mammalian spinal cord. Trends neurosci 1990; 13(12): 499-505. [DOI:10.1016/0166-2236(90)90084-N]
51. Sluka KA, Willis WD, Westlund KN. Inflammation-induced release of excitatory amino acids is prevented by spinal administration of a GABAA but not by a GABAB receptor antagonist in rats. Journal of pharmacology and experimental therapeutics 1994; 271(1): 76-82 .
52. Obata K, Yamanaka H, Fukuoka T, Yi D, Tokunaga A, Hashimoto N, Yoshikawa H, Noguchi K. Contribution of injured and uninjured dorsal root ganglion neurons to pain behavior and the changes in gene expression following chronic constriction injury of the sciatic nerve in rats. Pain 2003; 101(1-2): 65-77. [DOI:10.1016/S0304-3959(02)00296-8]
53. Price TJ, Cervero F, Gold MS, Hammond DL, Prescott SA. Chloride regulation in the pain pathway. Brain research reviews 2009; 60(1): 149-170. [DOI:10.1016/j.brainresrev.2008.12.015]
54. Janssen S, Truin M, Van Kleef M, Joosten E. Differential GABAergic disinhibition during the development of painful peripheral neuropathy. Neuroscience 2011; 184: 183-194. [DOI:10.1016/j.neuroscience.2011.03.060]

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.