Dietary polyphenols as a safe and novel intervention for modulating pain associated with intervertebral disc degeneration in an in-vivo rat model

Autoři: Alon Lai aff001;  Lap Ho aff002;  Thomas W. Evashwick-Rogler aff001;  Hironobu Watanabe aff004;  Jonathan Salandra aff005;  Beth A. Winkelstein aff006;  Damien Laudier aff001;  Andrew C. Hecht aff001;  Giulio M. Pasinetti aff002;  James C. Iatridis aff001
Působiště autorů: Leni & Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America aff001;  Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America aff002;  James J. Peters Veterans Affairs Medical Center, Bronx, New York, United States of America aff003;  Keiyu Orthopedic Hospital, Tatebayashi, Japan aff004;  Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, United States of America aff005;  Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff006
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article


Developing effective therapies for back pain associated with intervertebral disc (IVD) degeneration is a research priority since it is a major socioeconomic burden and current conservative and surgical treatments have limited success. Polyphenols are naturally occurring compounds in plant-derived foods and beverages, and evidence suggests dietary supplementation with select polyphenol preparations can modulate diverse neurological and painful disorders. This study tested whether supplementation with a select standardized Bioactive-Dietary-Polyphenol-Preparation (BDPP) may alleviate pain symptoms associated with IVD degeneration. Painful IVD degeneration was surgically induced in skeletally-mature rats by intradiscal saline injection into three consecutive lumbar IVDs. Injured rats were given normal or BDPP-supplemented drinking water. In-vivo hindpaw mechanical allodynia and IVD height were assessed weekly for 6 weeks following injury. Spinal column, dorsal-root-ganglion (DRG) and serum were collected at 1 and 6 weeks post-operative (post-op) for analyses of IVD-related mechanical and biological pathogenic processes. Dietary BDPP significantly alleviated the typical behavioral sensitivity associated with surgical procedures and IVD degeneration, but did not modulate IVD degeneration nor changes of pro-inflammatory cytokine levels in IVD. Gene expression analyses suggested BDPP might have an immunomodulatory effect in attenuating the expression of pro-inflammatory cytokines in DRGs. This study supports the idea that dietary supplementation with BDPP has potential to alleviate IVD degeneration-related pain, and further investigations are warranted to identify the mechanisms of action of dietary BDPP.

Klíčová slova:

Cytokines – Gene expression – Inflammation – Neurons – Pain sensation – Rats – Surgical and invasive medical procedures – Allodynia


1. Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2163–96. doi: 10.1016/S0140-6736(12)61729-2 23245607; PubMed Central PMCID: PMC6350784.

2. Livshits G, Popham M, Malkin I, Sambrook PN, Macgregor AJ, Spector T, et al. Lumbar disc degeneration and genetic factors are the main risk factors for low back pain in women: the UK Twin Spine Study. Annals of the rheumatic diseases. 2011;70(10):1740–5. doi: 10.1136/ard.2010.137836 21646416; PubMed Central PMCID: PMC3171106.

3. Adams MA, Roughley PJ. What is intervertebral disc degeneration, and what causes it? Spine. 2006;31(18):2151–61. doi: 10.1097/01.brs.0000231761.73859.2c 16915105.

4. Mosley GE, Evashwick-Rogler TW, Lai A, Iatridis JC. Looking beyond the intervertebral disc: the need for behavioral assays in models of discogenic pain. Ann N Y Acad Sci. 2017. doi: 10.1111/nyas.13429 28797134.

5. Hartvigsen J, Hancock MJ, Kongsted A, Louw Q, Ferreira ML, Genevay S, et al. What low back pain is and why we need to pay attention. Lancet. 2018;391(10137):2356–67. doi: 10.1016/S0140-6736(18)30480-X 29573870.

6. Hall H, McIntosh G. Low back pain (chronic). BMJ Clin Evid. 2008;2008. 19445791; PubMed Central PMCID: PMC2908004.

7. Brox JI, Nygaard OP, Holm I, Keller A, Ingebrigtsen T, Reikeras O. Four-year follow-up of surgical versus non-surgical therapy for chronic low back pain. Ann Rheum Dis. 2010;69(9):1643–8. doi: 10.1136/ard.2009.108902 19635718; PubMed Central PMCID: PMC2938881.

8. Foster NE, Anema JR, Cherkin D, Chou R, Cohen SP, Gross DP, et al. Prevention and treatment of low back pain: evidence, challenges, and promising directions. Lancet. 2018;391(10137):2368–83. doi: 10.1016/S0140-6736(18)30489-6 29573872.

9. Buckley CT, Hoyland JA, Fujii K, Pandit A, Iatridis JC, Grad S. Critical aspects and challenges for intervertebral disc repair and regeneration—Harnessing advances in tissue engineering. JOR Spine. 2018;1(3):e1029. doi: 10.1002/jsp2.1029 30895276

10. Sivaprakasapillai B, Edirisinghe I, Randolph J, Steinberg F, Kappagoda T. Effect of grape seed extract on blood pressure in subjects with the metabolic syndrome. Metabolism. 2009;58(12):1743–6. Epub 2009/07/18. doi: 10.1016/j.metabol.2009.05.030 19608210.

11. Krikorian R, Boespflug EL, Fleck DE, Stein AL, Wightman JD, Shidler MD, et al. Concord grape juice supplementation and neurocognitive function in human aging. J Agric Food Chem. 2012;60(23):5736–42. Epub 2012/04/04. doi: 10.1021/jf300277g 22468945.

12. Xia EQ, Deng GF, Guo YJ, Li HB. Biological activities of polyphenols from grapes. Int J Mol Sci. 2010;11(2):622–46. Epub 2010/04/14. doi: 10.3390/ijms11020622 20386657; PubMed Central PMCID: PMC2852857.

13. Aziz MH, Afaq F, Ahmad N. Prevention of ultraviolet-B radiation damage by resveratrol in mouse skin is mediated via modulation in survivin. Photochem Photobiol. 2005;81(1):25–31. doi: 10.1562/2004-08-13-RA-274 15469386.

14. Kundu JK, Shin YK, Surh YJ. Resveratrol modulates phorbol ester-induced pro-inflammatory signal transduction pathways in mouse skin in vivo: NF-kappaB and AP-1 as prime targets. Biochem Pharmacol. 2006;72(11):1506–15. doi: 10.1016/j.bcp.2006.08.005 16999939.

15. Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol. 2011;82(12):1807–21. doi: 10.1016/j.bcp.2011.07.093 21827739; PubMed Central PMCID: PMC4082721.

16. Wang J, Tang C, Ferruzzi MG, Gong B, Song BJ, Janle EM, et al. Role of standardized grape polyphenol preparation as a novel treatment to improve synaptic plasticity through attenuation of features of metabolic syndrome in a mouse model. Mol Nutr Food Res. 2013;57(12):2091–102. doi: 10.1002/mnfr.201300230 23963661; PubMed Central PMCID: PMC3855562.

17. Ho L, Ferruzzi MG, Janle EM, Wang J, Gong B, Chen TY, et al. Identification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novel intervention for Alzheimer's disease. FASEB J. 2013;27(2):769–81. doi: 10.1096/fj.12-212118 23097297; PubMed Central PMCID: PMC3545533.

18. Wuertz K, Quero L, Sekiguchi M, Klawitter M, Nerlich A, Konno S, et al. The red wine polyphenol resveratrol shows promising potential for the treatment of nucleus pulposus-mediated pain in vitro and in vivo. Spine (Phila Pa 1976). 2011;36(21):E1373–84. doi: 10.1097/BRS.0b013e318221e655 21587103.

19. Krupkova O, Sekiguchi M, Klasen J, Hausmann O, Konno S, Ferguson SJ, et al. Epigallocatechin 3-gallate suppresses interleukin-1beta-induced inflammatory responses in intervertebral disc cells in vitro and reduces radiculopathic pain in rats. Eur Cell Mater. 2014;28:372–86. 25422948.

20. Shakibaei M, Csaki C, Nebrich S, Mobasheri A. Resveratrol suppresses interleukin-1beta-induced inflammatory signaling and apoptosis in human articular chondrocytes: potential for use as a novel nutraceutical for the treatment of osteoarthritis. Biochem Pharmacol. 2008;76(11):1426–39. doi: 10.1016/j.bcp.2008.05.029 18606398.

21. Jaumard NV, Leung J, Gokhale AJ, Guarino BB, Welch WC, Winkelstein BA. Relevant Anatomic and Morphological Measurements of the Rat Spine: Considerations for Rodent Models of Human Spine Trauma. Spine (Phila Pa 1976). 2015;40(20):E1084–92. doi: 10.1097/BRS.0000000000001021 26731709.

22. Lai A, Moon A, Purmessur D, Skovrlj B, Winkelstein BA, Cho SK, et al. Assessment of functional and behavioral changes sensitive to painful disc degeneration. J Orthop Res. 2015;33(5):755–64. doi: 10.1002/jor.22833 25731955; PubMed Central PMCID: PMC4406864.

23. Lai A, Moon A, Purmessur D, Skovrlj B, Laudier DM, Winkelstein BA, et al. Annular puncture with tumor necrosis factor-alpha injection enhances painful behavior with disc degeneration in vivo. Spine J. 2016;16(3):420–31. doi: 10.1016/j.spinee.2015.11.019 26610672; PubMed Central PMCID: PMC4913353.

24. Evashwick-Rogler TW, Lai A, Watanabe H, Salandra JM, Winkelstein BA, Cho SK, et al. Inhibiting tumor necrosis factor-alpha at time of induced intervertebral disc injury limits long-term pain and degeneration in a rat model. JOR Spine. 2018;1(2). doi: 10.1002/jsp2.1014 29963655; PubMed Central PMCID: PMC6022768.

25. Wang J, Bi W, Cheng A, Freire D, Vempati P, Zhao W, et al. Targeting multiple pathogenic mechanisms with polyphenols for the treatment of Alzheimer's disease-experimental approach and therapeutic implications. Front Aging Neurosci. 2014;6:42. doi: 10.3389/fnagi.2014.00042 24672477; PubMed Central PMCID: PMC3954102.

26. Zhao W, Wang J, Bi W, Ferruzzi M, Yemul S, Freire D, et al. Novel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunction. Neurochem Int. 2015;89:191–7. doi: 10.1016/j.neuint.2015.07.023 26235983; PubMed Central PMCID: PMC4891811.

27. Wang J, Ho L, Zhao W, Ono K, Rosensweig C, Chen L, et al. Grape-derived polyphenolics prevent Abeta oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimer's disease. J Neurosci. 2008;28(25):6388–92. doi: 10.1523/JNEUROSCI.0364-08.2008 18562609; PubMed Central PMCID: PMC2806059.

28. Wang J, Santa-Maria I, Ho L, Ksiezak-Reding H, Ono K, Teplow DB, et al. Grape derived polyphenols attenuate tau neuropathology in a mouse model of Alzheimer's disease. J Alzheimers Dis. 2010;22(2):653–61. doi: 10.3233/JAD-2010-101074 20858961.

29. Xu Y, Simon JE, Welch C, Wightman JD, Ferruzzi MG, Ho L, et al. Survey of polyphenol constituents in grapes and grape-derived products. J Agric Food Chem. 2011;59(19):10586–93. doi: 10.1021/jf202438d 21879745.

30. Ferruzzi MG, Lobo JK, Janle EM, Cooper B, Simon JE, Wu QL, et al. Bioavailability of gallic acid and catechins from grape seed polyphenol extract is improved by repeated dosing in rats: implications for treatment in Alzheimer's disease. J Alzheimers Dis. 2009;18(1):113–24. doi: 10.3233/JAD-2009-1135 19625746; PubMed Central PMCID: PMC2801429.

31. Lee M, Kim BJ, Lim EJ, Back SK, Lee JH, Yu SW, et al. Complete Freund's adjuvant-induced intervertebral discitis as an animal model for discogenic low back pain. Anesthesia and analgesia. 2009;109(4):1287–96. Epub 2009/09/19. doi: 10.1213/ane.0b013e3181b31f39 19762759.

32. Kim JS, Kroin JS, Li X, An HS, Buvanendran A, Yan D, et al. The rat intervertebral disk degeneration pain model: relationships between biological and structural alterations and pain. Arthritis Res Ther. 2011;13(5):R165. Epub 2011/10/15. doi: 10.1186/ar3485 21996269.

33. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53(1):55–63. Epub 1994/07/01. 0165-0270(94)90144-9 [pii]. doi: 10.1016/0165-0270(94)90144-9 7990513.

34. Lai A, Chow DH, Siu WS, Holmes AD, Tang FH. Reliability of radiographic intervertebral disc height measurement for in vivo rat-tail model. Med Eng Phys. 2007;29(7):814–9. doi: 10.1016/j.medengphy.2006.08.013 17023188.

35. Masuda K, Aota Y, Muehleman C, Imai Y, Okuma M, Thonar EJ, et al. A novel rabbit model of mild, reproducible disc degeneration by an anulus needle puncture: correlation between the degree of disc injury and radiological and histological appearances of disc degeneration. Spine (Phila Pa 1976). 2005;30(1):5–14. doi: 10.1097/01.brs.0000148152.04401.20 15626974.

36. Rutges JP, Duit RA, Kummer JA, Bekkers JE, Oner FC, Castelein RM, et al. A validated new histological classification for intervertebral disc degeneration. Osteoarthritis Cartilage. 2013;21(12):2039–47. doi: 10.1016/j.joca.2013.10.001 24120397.

37. Ohtori S, Takahashi Y, Takahashi K, Yamagata M, Chiba T, Tanaka K, et al. Sensory innervation of the dorsal portion of the lumbar intervertebral disc in rats. Spine (Phila Pa 1976). 1999;24(22):2295–9. doi: 10.1097/00007632-199911150-00002 10586451.

38. Ohtori S, Takahashi K, Chiba T, Yamagata M, Sameda H, Moriya H. Sensory innervation of the dorsal portion of the lumbar intervertebral discs in rats. Spine (Phila Pa 1976). 2001;26(8):946–50. doi: 10.1097/00007632-200104150-00020 11317119.

39. Weisshaar CL, Dong L, Bowman AS, Perez FM, Guarino BB, Sweitzer SM, et al. Metabotropic glutamate receptor-5 and protein kinase C-epsilon increase in dorsal root ganglion neurons and spinal glial activation in an adolescent rat model of painful neck injury. J Neurotrauma. 2010;27(12):2261–71. doi: 10.1089/neu.2010.1460 20925479.

40. Dong L, Quindlen JC, Lipschutz DE, Winkelstein BA. Whiplash-like facet joint loading initiates glutamatergic responses in the DRG and spinal cord associated with behavioral hypersensitivity. Brain Res. 2012;1461:51–63. doi: 10.1016/j.brainres.2012.04.026 22578356; PubMed Central PMCID: PMC3368099.

41. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139(2):267–84. doi: 10.1016/j.cell.2009.09.028 19837031; PubMed Central PMCID: PMC2852643.

42. Michalek AJ, Funabashi KL, Iatridis JC. Needle puncture injury of the rat intervertebral disc affects torsional and compressive biomechanics differently. Eur Spine J. 2010;19(12):2110–6. Epub 2010/06/15. doi: 10.1007/s00586-010-1473-z 20544231; PubMed Central PMCID: PMC2997207.

43. Elliott DM, Yerramalli CS, Beckstein JC, Boxberger JI, Johannessen W, Vresilovic EJ. The effect of relative needle diameter in puncture and sham injection animal models of degeneration. Spine (Phila Pa 1976). 2008;33(6):588–96. Epub 2008/03/18. doi: 10.1097/BRS.0b013e318166e0a2 18344851.

44. Freemont AJ, Peacock TE, Goupille P, Hoyland JA, O'Brien J, Jayson MI. Nerve ingrowth into diseased intervertebral disc in chronic back pain. Lancet. 1997;350(9072):178–81. doi: 10.1016/s0140-6736(97)02135-1 9250186.

45. Boden SD, Davis DO, Dina TS, Patronas NJ, Wiesel SW. Abnormal magnetic-resonance scans of the lumbar spine in asymptomatic subjects. A prospective investigation. The Journal of bone and joint surgery. 1990;72(3):403–8. 2312537.

46. Ulrich JA, Liebenberg EC, Thuillier DU, Lotz JC. ISSLS prize winner: repeated disc injury causes persistent inflammation. Spine (Phila Pa 1976). 2007;32(25):2812–9. Epub 2008/02/05. doi: 10.1097/BRS.0b013e31815b9850 18246002.

47. Miyagi M, Ishikawa T, Orita S, Eguchi Y, Kamoda H, Arai G, et al. Disk injury in rats produces persistent increases in pain-related neuropeptides in dorsal root ganglia and spinal cord glia but only transient increases in inflammatory mediators: pathomechanism of chronic diskogenic low back pain. Spine (Phila Pa 1976). 2011;36(26):2260–6. Epub 2011/01/14. doi: 10.1097/BRS.0b013e31820e68c7 21228748.

48. Chen TY, Ferruzzi MG, Wu QL, Simon JE, Talcott ST, Wang J, et al. Influence of diabetes on plasma pharmacokinetics and brain bioavailability of grape polyphenols and their phase II metabolites in the Zucker diabetic fatty rat. Mol Nutr Food Res. 2017;61(10). doi: 10.1002/mnfr.201700111 28568316; PubMed Central PMCID: PMC5635601.

49. Johnson WD, Morrissey RL, Usborne AL, Kapetanovic I, Crowell JA, Muzzio M, et al. Subchronic oral toxicity and cardiovascular safety pharmacology studies of resveratrol, a naturally occurring polyphenol with cancer preventive activity. Food Chem Toxicol. 2011;49(12):3319–27. doi: 10.1016/j.fct.2011.08.023 21939727; PubMed Central PMCID: PMC3223276.

50. Wren AF, Cleary M, Frantz C, Melton S, Norris L. 90-day oral toxicity study of a grape seed extract (IH636) in rats. J Agric Food Chem. 2002;50(7):2180–92. doi: 10.1021/jf011066w 11902976.

51. National Research Council Committee on Pesticides in the Diets of Infants and Children. Pesticides in the Diets of Infants and Children. Washington (DC): National Academy Press; 1993.

52. Frolinger T, Herman F, Sharma A, Sims S, Wang J, Pasinetti GM. Epigenetic modifications by polyphenolic compounds alter gene expression in the hippocampus. Biol Open. 2018;7(10). doi: 10.1242/bio.035196 29970476; PubMed Central PMCID: PMC6215408.

53. Frolinger T, Smith C, Cobo CF, Sims S, Brathwaite J, de Boer S, et al. Dietary polyphenols promote resilience against sleep deprivation-induced cognitive impairment by activating protein translation. FASEB J. 2018;32(10):5390–404. doi: 10.1096/fj.201800030R 29702026; PubMed Central PMCID: PMC6133707.

54. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7(2):27–31. doi: 10.4103/0976-0105.177703 27057123; PubMed Central PMCID: PMC4804402.

55. Han B, Zhu K, Li FC, Xiao YX, Feng J, Shi ZL, et al. A simple disc degeneration model induced by percutaneous needle puncture in the rat tail. Spine (Phila Pa 1976). 2008;33(18):1925–34. Epub 2008/08/19. doi: 10.1097/BRS.0b013e31817c64a9 18708924.

56. Hsieh AH, Hwang D, Ryan DA, Freeman AK, Kim H. Degenerative anular changes induced by puncture are associated with insufficiency of disc biomechanical function. Spine (Phila Pa 1976). 2009;34(10):998–1005. Epub 2009/05/01. doi: 10.1097/BRS.0b013e31819c09c4 19404174.

57. Elmali N, Esenkaya I, Harma A, Ertem K, Turkoz Y, Mizrak B. Effect of resveratrol in experimental osteoarthritis in rabbits. Inflamm Res. 2005;54(4):158–62. Epub 2005/05/11. doi: 10.1007/s00011-004-1341-6 15883738.

58. Hadipour-Jahromy M, Mozaffari-Kermani R. Chondroprotective effects of pomegranate juice on monoiodoacetate-induced osteoarthritis of the knee joint of mice. Phytother Res. 2010;24(2):182–5. Epub 2009/06/09. doi: 10.1002/ptr.2880 19504467.

59. Wang J, Gao JS, Chen JW, Li F, Tian J. Effect of resveratrol on cartilage protection and apoptosis inhibition in experimental osteoarthritis of rabbit. Rheumatol Int. 2012;32(6):1541–8. Epub 2011/02/18. doi: 10.1007/s00296-010-1720-y 21327438.

60. Gordon FT, Soliman MR. The effects of estradiol and progesterone on pain sensitivity and brain opioid receptors in ovariectomized rats. Horm Behav. 1996;30(3):244–50. doi: 10.1006/hbeh.1996.0029 8918680.

61. Frye CA, Seliga AM. Testosterone increases analgesia, anxiolysis, and cognitive performance of male rats. Cogn Affect Behav Neurosci. 2001;1(4):371–81. 12467088.

62. LaCroix-Fralish ML, Rutkowski MD, Weinstein JN, Mogil JS, Deleo JA. The magnitude of mechanical allodynia in a rodent model of lumbar radiculopathy is dependent on strain and sex. Spine (Phila Pa 1976). 2005;30(16):1821–7. doi: 10.1097/01.brs.0000174122.63291.38 16103850.

63. Sorge RE, Totsch SK. Sex Differences in Pain. J Neurosci Res. 2017;95(6):1271–81. doi: 10.1002/jnr.23841 27452349.

64. Mogil JS, Bailey AL. Sex and gender differences in pain and analgesia. Prog Brain Res. 2010;186:141–57. doi: 10.1016/B978-0-444-53630-3.00009-9 21094890.

65. Mosley GE, Hoy RC, Nasser P, Kaseta T, Lai A, Evashwick-Rogler TW, et al. Sex Differences in Rat Intervertebral Disc Structure and Function Following Annular Puncture Injury. Spine (Phila Pa 1976). 2019. doi: 10.1097/BRS.0000000000003055 30973506.

66. Assas BM, Pennock JI, Miyan JA. Calcitonin gene-related peptide is a key neurotransmitter in the neuro-immune axis. Front Neurosci. 2014;8:23. doi: 10.3389/fnins.2014.00023 24592205; PubMed Central PMCID: PMC3924554.

67. Miyagi M, Ishikawa T, Kamoda H, Suzuki M, Murakami K, Shibayama M, et al. ISSLS prize winner: disc dynamic compression in rats produces long-lasting increases in inflammatory mediators in discs and induces long-lasting nerve injury and regeneration of the afferent fibers innervating discs: a pathomechanism for chronic discogenic low back pain. Spine (Phila Pa 1976). 2012;37(21):1810–8. doi: 10.1097/BRS.0b013e31824ffac6 22366969.

68. Luchtmann M, Steinecke Y, Baecke S, Lutzkendorf R, Bernarding J, Kohl J, et al. Structural brain alterations in patients with lumbar disc herniation: a preliminary study. PLoS One. 2014;9(3):e90816. doi: 10.1371/journal.pone.0090816 24595036; PubMed Central PMCID: PMC3940958.

69. Luchtmann M, Firsching R. Central plasticity resulting from chronic low back pain in degenerative disorders of the spine. Neural Regen Res. 2015;10(8):1234–6. doi: 10.4103/1673-5374.162754 26487848; PubMed Central PMCID: PMC4590233.

70. Janle EM, Lila MA, Grannan M, Wood L, Higgins A, Yousef GG, et al. Pharmacokinetics and tissue distribution of 14C-labeled grape polyphenols in the periphery and the central nervous system following oral administration. J Med Food. 2010;13(4):926–33. doi: 10.1089/jmf.2009.0157 20673061; PubMed Central PMCID: PMC3132945.

71. Apkarian AV, Lavarello S, Randolf A, Berra HH, Chialvo DR, Besedovsky HO, et al. Expression of IL-1beta in supraspinal brain regions in rats with neuropathic pain. Neurosci Lett. 2006;407(2):176–81. doi: 10.1016/j.neulet.2006.08.034 16973269; PubMed Central PMCID: PMC1851944.

72. Ignatowski TA, Covey WC, Knight PR, Severin CM, Nickola TJ, Spengler RN. Brain-derived TNFalpha mediates neuropathic pain. Brain Res. 1999;841(1–2):70–7. doi: 10.1016/s0006-8993(99)01782-5 10546989.

73. Ignatowski TA, Sud R, Reynolds JL, Knight PR, Spengler RN. The dissipation of neuropathic pain paradoxically involves the presence of tumor necrosis factor-alpha (TNF). Neuropharmacology. 2005;48(3):448–60. doi: 10.1016/j.neuropharm.2004.11.001 15721177.

74. Covey WC, Ignatowski TA, Knight PR, Spengler RN. Brain-derived TNFalpha: involvement in neuroplastic changes implicated in the conscious perception of persistent pain. Brain Res. 2000;859(1):113–22. doi: 10.1016/s0006-8993(00)01965-x 10720620.

75. Al-Amin H, Sarkis R, Atweh S, Jabbur S, Saade N. Chronic dizocilpine or apomorphine and development of neuropathy in two animal models II: effects on brain cytokines and neurotrophins. Exp Neurol. 2011;228(1):30–40. doi: 10.1016/j.expneurol.2010.11.005 21075106.

76. Blom SM, Pfister JP, Santello M, Senn W, Nevian T. Nerve injury-induced neuropathic pain causes disinhibition of the anterior cingulate cortex. J Neurosci. 2014;34(17):5754–64. doi: 10.1523/JNEUROSCI.3667-13.2014 24760836.

77. Rusanescu G, Mao J. Peripheral nerve injury induces adult brain neurogenesis and remodelling. J Cell Mol Med. 2016. doi: 10.1111/jcmm.12965 27665307.

78. Price J. An immunohistochemical and quantitative examination of dorsal root ganglion neuronal subpopulations. J Neurosci. 1985;5(8):2051–9. 2410579.

79. Xu ZZ, Kim YH, Bang S, Zhang Y, Berta T, Wang F, et al. Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nat Med. 2015;21(11):1326–31. doi: 10.1038/nm.3978 26479925; PubMed Central PMCID: PMC4752254.

80. Li CL, Li KC, Wu D, Chen Y, Luo H, Zhao JR, et al. Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity. Cell Res. 2016;26(8):967. doi: 10.1038/cr.2016.90 27481604; PubMed Central PMCID: PMC4973338.

Článek vyšel v časopise


2019 Číslo 10
Nejčtenější tento týden