ppanPersonalized Psychiatry and NeurologyPersonalized Psychiatry and Neurology2712-9179V. M. Bekhterev National Medical Research Centre for Psychiatry and Neurology of the Ministry of Health of the Russian Federation (Bekhterev NMRC PN)10.52667/2712-9179-2021-1-1-37-45ppan-9Research ArticleREVIEWThe role of NO system in low back pain chronicityTrefilovaV. V.

Vera V. Trefilova

193079, St. Petersburg, Tel.: +7-(812)-670-89-37

vermutdoc@gmai1.comShnayderN. A.

Natalia A. Shnayder

Saint-Petersburg, Tel.: +7-(812)-620-02-20; 660022, Krasnoyarsk

nataliashnayder@gmail.comPopovaT. E.

Tatyana E. Popova

677000, Yakutsk

ynckmp@yandex.ruBalberovaO. V.

Olga V. Balberova

454091, Chelyabinsk

uralacad-emy@mail.ruNasyrovaR. F.

Regina F. Nasyrova

Saint-Petersburg, Tel.: +7-(812)-620-02-20

nreginaf77@gmail.comThe Hospital for War Veterans; V.M. Bekhterev National Research Medical Center for Psychiatry and NeurologyRussian FederationV.M. Bekhterev National Research Medical Center for Psychiatry and Neurology; V.F. Voino-Yasenetsky Krasnoyarsk State Medical UniversityRussian FederationYakutsk Scientific Center for Complex Medical ProblemsRussian FederationThe Ural State University of Physical CultureRussian FederationV.M. Bekhterev National Research Medical Center for Psychiatry and NeurologyRussian Federation202115052021113745Copyright © Trefilova V.V., Shnayder N.A., Popova T.E., Balberova O.V., Nasyrova R.F., 20212021Trefilova V.V., Shnayder N.A., Popova T.E., Balberova O.V., Nasyrova R.F.Trefilova V.V., Shnayder N.A., Popova T.E., Balberova O.V., Nasyrova R.F.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.jppn.ru/jour/article/view/9

Low back pain (LBP) is an important interdisciplinary medical problem, in the development of which various molecular genetics, pathomorphological and pathobiomechanical mechanisms play a role. Intervertebral disc degeneration (IVDD), facet joints arthrosis and myofascial syndrome are the most important pathological processes associated with chronic lower back pain in adults. The nitric oxide (NO) system may play one of the key roles in the development of LBP and its chronicity. (1): Background: The review of publications which are devoted to changes in the NO system in patients with LBP. (2): Materials: We have carried out a search for Russian-language and English-language full-text articles published in e-Library, PubMed, Oxford Press, Clinical Case, Springer, Elsevier, Google Scholar databases. The search was carried out using keywords and their combinations. The search depth was 10 years (2011-2021). (3): Results: Role of NO and various NOsynthase (NOS) isoforms in LBP process demonstrated primarily from animal models to humans. The most studied are the neuronal NOS (nNOS). The role of inducible nose (iNOS) and endothelial (eNOS) - continues to be studied. Associative genetic studies have shown that single nucleotide variants (SNV) of genes encoding all three NOS isoforms (nNOS, NOS1 gene; iNOS, NOS2 gene; eNOS, NOS3 gene) may be associated with chronic LBP. Prospects for the use of NOS inhibitors to modulate the effect of drugs used to treat back pain are discussed. (4): Conclusion: Associative genetic studies of SNV NOS1, NOS2, NOS3 genes are important for understanding genetic predictors of LBP chronicity and development of new personalized pharmacotherapy strategies.

intervertebral discdegenerationfacet joints arthrosismyofascial syndromelow back painnitric oxidenitric oxide synthase (NOS)genegeneticsgenetic predispositionThe authors thank Evgeniy A. Trevilov for the technical assistance in preparing all the figuresReferencesHartvigsen, J.; Hancock, M.J.; Kongsted, A.; Louw, Q.; Ferreira, M.L.; Genevay, S.; Hoy, D.; Karppinen, J.; Pransky, G.; Sieper, J.; Smeets, R.J.; Underwood, M. Lancet Low Back Pain Series Working Group. What low back pain is and why we need to pay attention. Lancet 2018, 391, 2356-2367, doi:10.1016/S0140-6736(18)30480-X.Hartvigsen, J.; Hancock, M.J.; Kongsted, A.; Louw, Q.; Ferreira, M.L.; Genevay, S.; Hoy, D.; Karppinen, J.; Pransky, G.; Sieper, J.; Smeets, R.J.; Underwood, M. Lancet Low Back Pain Series Working Group. What low back pain is and why we need to pay attention. Lancet 2018, 391, 2356-2367, doi:10.1016/S0140-6736(18)30480-X.Alleva, J.; Hudgins, T.; Belous, J.; Kristin Origenes A. Chronic low back pain. Dis Mon. 2016, 62, 330-333, doi:10.1016/j.dis-amonth.2016.05.012.Alleva, J.; Hudgins, T.; Belous, J.; Kristin Origenes A. Chronic low back pain. Dis Mon. 2016, 62, 330-333, doi:10.1016/j.dis-amonth.2016.05.012.Urits, I.; Burshtein, A.; Sharma, M.; Testa, L.; Gold, P.A.; Orhurhu, V.; Viswanath, O.; Jones, M.R.; Sidransky, M.A.; Spektor, B.; Kaye, A.D. Low Back Pain, a Comprehensive Review: Pathophysiology, Diagnosis, and Treatment. Curr Pain Headache Rep. 2019, 23, 23, doi:10.1007/s11916-019-0757-1. PMID: 30854609.Urits, I.; Burshtein, A.; Sharma, M.; Testa, L.; Gold, P.A.; Orhurhu, V.; Viswanath, O.; Jones, M.R.; Sidransky, M.A.; Spektor, B.; Kaye, A.D. Low Back Pain, a Comprehensive Review: Pathophysiology, Diagnosis, and Treatment. Curr Pain Headache Rep. 2019, 23, 23, doi:10.1007/s11916-019-0757-1. PMID: 30854609.Zinovieva, O.E.; Rozhkov, D.O. Multidisciplinary approach to the treatment of chronic nonspecific back pain. Analysis of the clinical case. RMJ. 2018, 4, 93-96.Zinovieva, O.E.; Rozhkov, D.O. Multidisciplinary approach to the treatment of chronic nonspecific back pain. Analysis of the clinical case. RMJ. 2018, 4, 93-96.Motina, A.N.; Astashchenko, Ya.A.; Masaleva, I.O.; Tretyakova E.E. The social hygienic characteristic of patients with osteochondrosis of spine. Probl Sotsialnoi Gig Zdravookhranenniiai Istor Med. 2020, 28, 396-399, Russian, doi:10.32687/0869-866X-2020-28-3-396-399.Motina, A.N.; Astashchenko, Ya.A.; Masaleva, I.O.; Tretyakova E.E. The social hygienic characteristic of patients with osteochondrosis of spine. Probl Sotsialnoi Gig Zdravookhranenniiai Istor Med. 2020, 28, 396-399, Russian, doi:10.32687/0869-866X-2020-28-3-396-399.Dagenais, S.; Caro, J.; Haldeman, S.; A systematic review of low back pain cost of illness studies in the United States and internationally. Spine J. 2008, 8, 8-20, doi:10.1016/j.spinee.2007.10.005.Dagenais, S.; Caro, J.; Haldeman, S.; A systematic review of low back pain cost of illness studies in the United States and internationally. Spine J. 2008, 8, 8-20, doi:10.1016/j.spinee.2007.10.005.Balyazin, V. Pain — multidisciplinary problem of medicine. Chief physician of the south of Russia 2018, 2, 4-6, Russian.Balyazin, V. Pain — multidisciplinary problem of medicine. Chief physician of the south of Russia 2018, 2, 4-6, Russian.Dutmer, A.L.; Schiphorst, P.; Henrica, R.; Soer, R.; Brouwer, S.; Bultmann, U.; Dijkstra, P.U.; Coppes, M.H.; Stegeman, P.; Buskens, E.; van Asselt, A.D.I.; Wolff, A.P.; Reneman, M.F. Personal and Societal Impact of Low Back Pain. Spine 2019, 44, 14431451, doi:10.1097/BRS.0000000000003174.Dutmer, A.L.; Schiphorst, P.; Henrica, R.; Soer, R.; Brouwer, S.; Bultmann, U.; Dijkstra, P.U.; Coppes, M.H.; Stegeman, P.; Buskens, E.; van Asselt, A.D.I.; Wolff, A.P.; Reneman, M.F. Personal and Societal Impact of Low Back Pain. Spine 2019, 44, 14431451, doi:10.1097/BRS.0000000000003174.Kang, J.D.; Stefanovic-Racic, M.; McIntyre, L.A; Georgescu, H.I.; Evans, C.H. Toward a biochemical understanding of human intervertebral disc degeneration and herniation. Contributions of nitric oxide, interleukins, prostaglandin E2, and matrix met-allopro-teinases. Spine (Phila Pa 1976) 1997, 22, 1065-1073, doi:10.1097/00007632-199705150-00003.Kang, J.D.; Stefanovic-Racic, M.; McIntyre, L.A; Georgescu, H.I.; Evans, C.H. Toward a biochemical understanding of human intervertebral disc degeneration and herniation. Contributions of nitric oxide, interleukins, prostaglandin E2, and matrix met-allopro-teinases. Spine (Phila Pa 1976) 1997, 22, 1065-1073, doi:10.1097/00007632-199705150-00003.Gonzalez-Castro, T.B.; Genis-Mendoza, A.D.; Tovilla-Zarate, C.A.; Juarez-Rojop, I.E.; Lopez-Narvaez, M.L.; Pe-rez-Hernandez, N.; Rodriguez-Perez, J.M.; Martmez-Magana, J.J. Association between polymorphisms of NOS1, NOS2 and NOS3 genes and suicide behavior: a systematic review and meta-analysis. Metab Brain Dis. 2019, 34, 967-977, doi:10.1007/s11011-019-00406-3.Gonzalez-Castro, T.B.; Genis-Mendoza, A.D.; Tovilla-Zarate, C.A.; Juarez-Rojop, I.E.; Lopez-Narvaez, M.L.; Pe-rez-Hernandez, N.; Rodriguez-Perez, J.M.; Martmez-Magana, J.J. Association between polymorphisms of NOS1, NOS2 and NOS3 genes and suicide behavior: a systematic review and meta-analysis. Metab Brain Dis. 2019, 34, 967-977, doi:10.1007/s11011-019-00406-3.Castania, V.; Issy, A.C.; Silveira, J.W.; et al. The Presence of the Neuronal Nitric Oxide Synthase Isoform in the Intervertebral Disk. Neurotox Res 2017, 31, 148-161, doi:10.1007/s12640-016-9676-7Castania, V.; Issy, A.C.; Silveira, J.W.; et al. The Presence of the Neuronal Nitric Oxide Synthase Isoform in the Intervertebral Disk. Neurotox Res 2017, 31, 148-161, doi:10.1007/s12640-016-9676-7Brisby, H.; Ashley, H.; Diwan, A.D. In vivo measurement of facet joint nitric oxide in patients with chronic low back pain. Spine (Phila Pa 1976) 2007, 32, 1488-1492, doi: 10.1097/BRS.0b013e318067dc97.Brisby, H.; Ashley, H.; Diwan, A.D. In vivo measurement of facet joint nitric oxide in patients with chronic low back pain. Spine (Phila Pa 1976) 2007, 32, 1488-1492, doi: 10.1097/BRS.0b013e318067dc97.Miclescu, A.; Gordh, T. Nitric oxide and pain: 'Something old, something new'. Acta Anaesthesiol Scand. 2009, 53, 1107-1120, doi:10.1111/j.1399-6576.2009.02054.x.Miclescu, A.; Gordh, T. Nitric oxide and pain: 'Something old, something new'. Acta Anaesthesiol Scand. 2009, 53, 1107-1120, doi:10.1111/j.1399-6576.2009.02054.x.Guhring, H.; Tegeder, I.; Lotsch, J.; Pahl, A.; Werner, U.; Reeh, P.W.; Rehse, K.; Brune, K.; Geisslinger, G. Role of nitric oxide in zymosan induced paw inflammation and thermal hyperalgesia. Inflamm Res. 2001, 50, 83-88, doi:10.1007/s000110050728.Guhring, H.; Tegeder, I.; Lotsch, J.; Pahl, A.; Werner, U.; Reeh, P.W.; Rehse, K.; Brune, K.; Geisslinger, G. Role of nitric oxide in zymosan induced paw inflammation and thermal hyperalgesia. Inflamm Res. 2001, 50, 83-88, doi:10.1007/s000110050728.De Alba, J.; Clayton, N.M.; Collins, S.D.; Colthup, P.; Chessell, I.; Knowles, R.G. GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), shows analgesic effects in rat models of inflammatory and neuropathic pain. Pain 2006, 120, 170-181, doi:10.1016/j.pain.2005.10.028.De Alba, J.; Clayton, N.M.; Collins, S.D.; Colthup, P.; Chessell, I.; Knowles, R.G. GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), shows analgesic effects in rat models of inflammatory and neuropathic pain. Pain 2006, 120, 170-181, doi:10.1016/j.pain.2005.10.028.Jensen, L.; Andersen, L.L.; Schrader, H.D.; Frandsen, U.; Sj0gaard, G. Neuronal nitric oxide synthase is dislocated in type I fibers of myalgic muscle but can recover with physical exercise training. Biomed Res Int. 2015, 26527, doi:10.1155/2015/265278.Jensen, L.; Andersen, L.L.; Schrader, H.D.; Frandsen, U.; Sj0gaard, G. Neuronal nitric oxide synthase is dislocated in type I fibers of myalgic muscle but can recover with physical exercise training. Biomed Res Int. 2015, 26527, doi:10.1155/2015/265278.Kohyama, K.; Saura, R.; Doita, M.; Mizuno, K. Intervertebral disc cell apoptosis by nitric oxide: biological understanding of intervertebral disc degeneration. Kobe J Med Sci. 2000, 46, 283-295.Kohyama, K.; Saura, R.; Doita, M.; Mizuno, K. Intervertebral disc cell apoptosis by nitric oxide: biological understanding of intervertebral disc degeneration. Kobe J Med Sci. 2000, 46, 283-295.Yang, X.; Jin, L.; Yao, L.; Shen, F.H.; Shimer, A.; Li, X. Antioxidative nanofullerol prevents intervertebral disk degeneration. Int J Nanomedicine. 2014, 9, 2419-2430, doi:10.2147/IJN.S60853.Yang, X.; Jin, L.; Yao, L.; Shen, F.H.; Shimer, A.; Li, X. Antioxidative nanofullerol prevents intervertebral disk degeneration. Int J Nanomedicine. 2014, 9, 2419-2430, doi:10.2147/IJN.S60853.Nerlich, A.G.; Bachmeier, B.E.; Schleicher, E.; Rohrbach H.; Paesold, G.; Boos, N. Immunomorphological analysis of RAGE receptor expression and NF-kappaB activation in tissue samples from normal and degenerated intervertebral discs of various ages. Ann N Y Acad Sci. 2007, 1096, 239-248, doi:10.1196/annals.1397.090.Nerlich, A.G.; Bachmeier, B.E.; Schleicher, E.; Rohrbach H.; Paesold, G.; Boos, N. Immunomorphological analysis of RAGE receptor expression and NF-kappaB activation in tissue samples from normal and degenerated intervertebral discs of various ages. Ann N Y Acad Sci. 2007, 1096, 239-248, doi:10.1196/annals.1397.090.Furusawa, N.; Baba, H.; Miyoshi, N; et al. Herniation of cervical intervertebral disc: immunohistochemical examination and measurement of nitric oxide production. Spine (Phila Pa 1976) 2001, 26, 1110-1116, doi:10.1097/00007632-200105150-00004.Furusawa, N.; Baba, H.; Miyoshi, N; et al. Herniation of cervical intervertebral disc: immunohistochemical examination and measurement of nitric oxide production. Spine (Phila Pa 1976) 2001, 26, 1110-1116, doi:10.1097/00007632-200105150-00004.Liu, G.Z.; Ishihara, H.; Osada, R.; Kimura, T.; Tsuji, H. Nitric oxide mediates the change of proteoglycan synthesis in the human lumbar intervertebral disc in response to hy-drostatic pressure. Spine (Phila Pa 1976) 2001, 26, 134-141, doi:10.1097/00007632-200101150-00005.Liu, G.Z.; Ishihara, H.; Osada, R.; Kimura, T.; Tsuji, H. Nitric oxide mediates the change of proteoglycan synthesis in the human lumbar intervertebral disc in response to hy-drostatic pressure. Spine (Phila Pa 1976) 2001, 26, 134-141, doi:10.1097/00007632-200101150-00005.Rannou, F.; Richette, P.; Benallaoua, M.; et al. Cyclic tensile stretch modulates proteoglycan production by intervertebral disc annulus fibrosus cells through production of nitrite oxide. J Cell Biochem. 2003, 90, 148-157, doi:10.1002/jcb.10608.Rannou, F.; Richette, P.; Benallaoua, M.; et al. Cyclic tensile stretch modulates proteoglycan production by intervertebral disc annulus fibrosus cells through production of nitrite oxide. J Cell Biochem. 2003, 90, 148-157, doi:10.1002/jcb.10608.Studer, R.K.; Gilbertson, L.G.; Georgescu, H.; Sowa, G.; Vo, N.; Kang J.D. p38 MAPK inhibition modulates rabbit nucleus pul-posus cell response to IL-1. J Orthop Res. 2008, 26, 991-998, doi:10.1002/jor.20604.Studer, R.K.; Gilbertson, L.G.; Georgescu, H.; Sowa, G.; Vo, N.; Kang J.D. p38 MAPK inhibition modulates rabbit nucleus pul-posus cell response to IL-1. J Orthop Res. 2008, 26, 991-998, doi:10.1002/jor.20604.Paz Aparicio, J.; Fernandez Bances, I.; Lopez-Anglada Fernandez, E.; Montes, A. H.; Paz Aparicio, A.; Pena Vazquez, J.; Ramos Garda, S.; Anton Garda, S.; Lopez Fernandez, P.; Valle-Garay, E.; Asensi, V. The IL-1p (+3953 T/C) gene polymorphism associates to symptomatic lumbar disc herniation. European spine journal 2011, 20 (Suppl. 3), 383-389, doi:10.1007/s00586-011-1915-2.Paz Aparicio, J.; Fernandez Bances, I.; Lopez-Anglada Fernandez, E.; Montes, A. H.; Paz Aparicio, A.; Pena Vazquez, J.; Ramos Garda, S.; Anton Garda, S.; Lopez Fernandez, P.; Valle-Garay, E.; Asensi, V. The IL-1p (+3953 T/C) gene polymorphism associates to symptomatic lumbar disc herniation. European spine journal 2011, 20 (Suppl. 3), 383-389, doi:10.1007/s00586-011-1915-2.Han, I.B.; Ropper, A.E.; Teng, Y.D.; Shin, D.A.; Jeon, Y.J.; Park, H.M.; Shin, D.E.; Park, Y.S.; Kim, K.N.; Kim, N.K. Association between VEGF and eNOS gene polymorphisms and lumbar disc degeneration in a young Korean population. Genet Mol Res. 2013, 12, 2294-2305, doi:10.4238/2013.July.8.10.Han, I.B.; Ropper, A.E.; Teng, Y.D.; Shin, D.A.; Jeon, Y.J.; Park, H.M.; Shin, D.E.; Park, Y.S.; Kim, K.N.; Kim, N.K. Association between VEGF and eNOS gene polymorphisms and lumbar disc degeneration in a young Korean population. Genet Mol Res. 2013, 12, 2294-2305, doi:10.4238/2013.July.8.10.Baldelli, S.; Lettieri Barbato, D.; Tatulli, G.; Aquilano, K.; Ciriolo, M.R. The role of nNOS and PGC-1a in skeletal muscle cells. J Cell Sci. 2014, 127, 4813-4820, doi:10.1242/jcs.154229.Baldelli, S.; Lettieri Barbato, D.; Tatulli, G.; Aquilano, K.; Ciriolo, M.R. The role of nNOS and PGC-1a in skeletal muscle cells. J Cell Sci. 2014, 127, 4813-4820, doi:10.1242/jcs.154229.Vandivier, R.W.; Eidsath, A.; Banks, S.M.; Preas, H.L.; 2nd, Leighton, S.B.; Godin, P.J.; Suffredini, A.F.; Danner, R.L. Down-regulation of nitric oxide production by ibuprofen in human volunteers. J Pharmacol Exp Ther. 1999, 289, 1398-1403.Vandivier, R.W.; Eidsath, A.; Banks, S.M.; Preas, H.L.; 2nd, Leighton, S.B.; Godin, P.J.; Suffredini, A.F.; Danner, R.L. Down-regulation of nitric oxide production by ibuprofen in human volunteers. J Pharmacol Exp Ther. 1999, 289, 1398-1403.Guhring, H.; Hamza, M.; Sergejeva, M.; Ates, M.; Kotalla, C.E.; Ledent, C.; Brune, K. A role for endocannabinoids in indometh-acin-induced spinal antinociception. Eur J Pharmacol. 2002, 454, 53-63, doi:10.1016/s0014-2999(02)02485-8.Guhring, H.; Hamza, M.; Sergejeva, M.; Ates, M.; Kotalla, C.E.; Ledent, C.; Brune, K. A role for endocannabinoids in indometh-acin-induced spinal antinociception. Eur J Pharmacol. 2002, 454, 53-63, doi:10.1016/s0014-2999(02)02485-8.Ryu, Y.S.; Lee, J.H.; Seok, J.H.; Hong, J.H.; Lee, Y.S.; Lim, J.H.; Kim, Y.M.; Hur, G.M. Acetaminophen inhibits iNOS gene expression in RAW 264.7 macrophages: differential regulation of NF-kappaB by acetaminophen and salicylates. Biochem Biophys Res Commun. 2000, 272, 758-764, doi:10.1006/bbrc.2000.2863.Ryu, Y.S.; Lee, J.H.; Seok, J.H.; Hong, J.H.; Lee, Y.S.; Lim, J.H.; Kim, Y.M.; Hur, G.M. Acetaminophen inhibits iNOS gene expression in RAW 264.7 macrophages: differential regulation of NF-kappaB by acetaminophen and salicylates. Biochem Biophys Res Commun. 2000, 272, 758-764, doi:10.1006/bbrc.2000.2863.Granados-Soto, V.; Flores-Murrieta, F.J.; Castaneda-Hernandez, G.; Lopez-Munoz, F.J. Evidence for the involvement of nitric oxide in the antinociceptive effect of ketorolac. Eur J Pharmacol. 1995, 277, 281-284, doi: 10.1016/0014-2999(95)00123-3.Granados-Soto, V.; Flores-Murrieta, F.J.; Castaneda-Hernandez, G.; Lopez-Munoz, F.J. Evidence for the involvement of nitric oxide in the antinociceptive effect of ketorolac. Eur J Pharmacol. 1995, 277, 281-284, doi: 10.1016/0014-2999(95)00123-3.Ventura-Martmez, R.; Deciga-Campos, M.; Dfaz-Reval, M.I.; Gonzalez-Trujano, M.E.; Lopez-Munoz, F.J. Peripheral involvement of the nitric oxide-cGMP pathway in the indomethacin-induced antinociception in rat. Eur J Pharmacol. 2004, 503, 43-48, doi:10.1016/j.ejphar.2004.09.018.Ventura-Martmez, R.; Deciga-Campos, M.; Dfaz-Reval, M.I.; Gonzalez-Trujano, M.E.; Lopez-Munoz, F.J. Peripheral involvement of the nitric oxide-cGMP pathway in the indomethacin-induced antinociception in rat. Eur J Pharmacol. 2004, 503, 43-48, doi:10.1016/j.ejphar.2004.09.018.Hamza, M.; Wang, X.M.; Wu, T.; Brahim, J.S.; Rowan, J.S.; Dionne, R.A. Nitric oxide is negatively correlated to pain during acute inflammation. Mol Pain. 2010, 6, 55, doi:10.1186/1744-8069-6-55.Hamza, M.; Wang, X.M.; Wu, T.; Brahim, J.S.; Rowan, J.S.; Dionne, R.A. Nitric oxide is negatively correlated to pain during acute inflammation. Mol Pain. 2010, 6, 55, doi:10.1186/1744-8069-6-55.Aley, K.O.; McCarter, G.; Levine, J.D. Nitric oxide signaling in pain and nociceptor sensitization in the rat. J Neurosci. 1998, 18, 7008-7014, doi:10.1523/JNEUROSCI.18-17-07008.1998.Aley, K.O.; McCarter, G.; Levine, J.D. Nitric oxide signaling in pain and nociceptor sensitization in the rat. J Neurosci. 1998, 18, 7008-7014, doi:10.1523/JNEUROSCI.18-17-07008.1998.Holthusen, H.; Arndt, J.O. Nitric oxide evokes pain in humans on intracutaneous injec-tion. Neurosci Lett. 1994, 165, 71-44, doi:10.1016/0304-3940(94)90712-9.Holthusen, H.; Arndt, J.O. Nitric oxide evokes pain in humans on intracutaneous injec-tion. Neurosci Lett. 1994, 165, 71-44, doi:10.1016/0304-3940(94)90712-9.Berrazueta, J.R.; Losada, A.; Poveda. J.; Ochoteco, A.; Riestra, A.; Salas, E.; Amado, J.A. Successful treatment of shoulder pain syndrome due to supraspinatus tendinitis with transdermal nitroglycerin. A double-blind study. Pain 1996, 66, 63-67, doi:10.1016/0304-3959(96)03021-7.Berrazueta, J.R.; Losada, A.; Poveda. J.; Ochoteco, A.; Riestra, A.; Salas, E.; Amado, J.A. Successful treatment of shoulder pain syndrome due to supraspinatus tendinitis with transdermal nitroglycerin. A double-blind study. Pain 1996, 66, 63-67, doi:10.1016/0304-3959(96)03021-7.Fujioka, Y.; Stahlberg, A.; Ochi, M.; Olmarker, K. Expression of inflammation/pain-related genes in the dorsal root ganglion following disc puncture in rats. J Orthop Surg. 2016, 24, 106-112, doi:10.1177/230949901602400124.Fujioka, Y.; Stahlberg, A.; Ochi, M.; Olmarker, K. Expression of inflammation/pain-related genes in the dorsal root ganglion following disc puncture in rats. J Orthop Surg. 2016, 24, 106-112, doi:10.1177/230949901602400124.Nerlich, A.G.; Schleicher, E.D.; Boos, N. Immunohistologic markers for age-related changes of human lumbar intervertebral discs. Spine (Phila Pa 1976) 1997, 22, 2781-2795, doi:10.1097/00007632-199712150-00001.Nerlich, A.G.; Schleicher, E.D.; Boos, N. Immunohistologic markers for age-related changes of human lumbar intervertebral discs. Spine (Phila Pa 1976) 1997, 22, 2781-2795, doi:10.1097/00007632-199712150-00001.Ziskoven, C.; Jager, M.; Kircher, J.; et al. Physiology and pathophysiology of nitrosative and oxidative stress in osteoarthritic joint destruction. Can J Physiol Pharmacol. 2011, 89, 455-466, doi:10.1139/y11-055.Ziskoven, C.; Jager, M.; Kircher, J.; et al. Physiology and pathophysiology of nitrosative and oxidative stress in osteoarthritic joint destruction. Can J Physiol Pharmacol. 2011, 89, 455-466, doi:10.1139/y11-055.Freemont, T.J.; LeMaitre, C.; Watkins, A.; Hoyland, J.A. Degeneration of intervertebral discs: current understanding of cellular and molecular events, and implications for novel therapies. Expert Rev Mol Med. 2001, 2001, 1-10, doi:10.1017/S1462399401002885.Freemont, T.J.; LeMaitre, C.; Watkins, A.; Hoyland, J.A. Degeneration of intervertebral discs: current understanding of cellular and molecular events, and implications for novel therapies. Expert Rev Mol Med. 2001, 2001, 1-10, doi:10.1017/S1462399401002885.Slade, S.C.; Keating, J.L. Unloaded movement facilitation exercise compared to no exercise or alternative therapy on outcomes for people with nonspecific chronic low back pain: a systematic review. J Manipulative Physiol Ther. 2007, 30, 301-311, doi:10.1016/j.jmpt.2007.03.010.Slade, S.C.; Keating, J.L. Unloaded movement facilitation exercise compared to no exercise or alternative therapy on outcomes for people with nonspecific chronic low back pain: a systematic review. J Manipulative Physiol Ther. 2007, 30, 301-311, doi:10.1016/j.jmpt.2007.03.010.Kim K.W.; Ha, K.Y.; Lee, J.S.; Rhyu, K.W.; An, H.S.; Woo, Y.K. The apoptotic effects of oxidative stress and antiapoptotic effects of caspase inhibitors on rat notochordal cells. Spine (Phila Pa 1976) 2007, 32, 2443-2448, doi:10.1097/BRS.0b013e318157395a.Kim K.W.; Ha, K.Y.; Lee, J.S.; Rhyu, K.W.; An, H.S.; Woo, Y.K. The apoptotic effects of oxidative stress and antiapoptotic effects of caspase inhibitors on rat notochordal cells. Spine (Phila Pa 1976) 2007, 32, 2443-2448, doi:10.1097/BRS.0b013e318157395a.Gruber, H.E.; Hoelscher, G.L.; Ingram, J.A.; Bethea, S.; Hanley, E.N. IGF-1 rescues human in-tervertebral annulus cells from in vitro stress-induced premature senescence. Growth Factors 2008, 26, 220-225, doi:10.1080/08977190802273814.Gruber, H.E.; Hoelscher, G.L.; Ingram, J.A.; Bethea, S.; Hanley, E.N. IGF-1 rescues human in-tervertebral annulus cells from in vitro stress-induced premature senescence. Growth Factors 2008, 26, 220-225, doi:10.1080/08977190802273814.

The authors declare that there are no conflicts of interest present.