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Probucol Ameliorates Complete Freund’s Adjuvant-Induced Hyperalgesia by Targeting Peripheral and Spinal Cord Inflammation

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Abstract

The effect of the lipid-lowering agent probucol in inflammatory hyperalgesia and leukocyte recruitment was evaluated in a model of subacute inflammation by Complete Freund’s adjuvant (CFA). As CFA induces long-lasting nociception characterized by peripheral and spinal cord inflammation, the anti-inflammatory activity of probucol was assessed at both foci. Probucol at 0.3–3 mg/kg was administrated per oral daily starting 24 h after CFA intraplantar injection. Mechanical and thermal hyperalgesia induced by CFA were determined using an electronic anesthesiometer and hot plate apparatus, respectively. Post-treatment with probucol at 3 mg/kg inhibited CFA-induced hyperalgesia over the course of 7 days as well as paw edema. Overt pain-like behaviors, which were determined by the number of flinches and time spent licking paw immediately following CFA injection, were also reduced by probucol at 3 mg/kg administered as a pre-treatment. To investigate the mechanisms underlying the analgesic effect of probucol, neutrophil recruitment to paw was assessed by myeloperoxidase activity, cytokine production, Cox-2 expression, and NF-κB activation in both paw and spinal cord by ELISA. Iba-1, GFAP, and substance P protein expression and nuclear localization of phosphorylated NF-κB were evaluated in the spinal cord by immunofluorescence. Probucol at 3 mg/kg attenuated neutrophil recruitment, cytokine levels, and NF-κB activation as well microglia and astrocyte activation, and substance P staining in the spinal cord. Taken together, the results suggest that probucol exerts its analgesic and anti-inflammatory activity in an experimental model of persistent inflammation by targeting the NF-κB pathway in peripheral and spinal cord foci.

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References

  1. Medzhitov, Ruslan. 2008. Origin and physiological roles of inflammation. Nature 454: 428–435. https://doi.org/10.1038/nature07201.

    Article  CAS  PubMed  Google Scholar 

  2. Ji, Ru-Rong, Zhen-Zhong Xu, and Yong-Jing Gao. 2014. Emerging targets in neuroinflammation-driven chronic pain. Nature Reviews Drug Discovery 13. NIH Public Access: 533–48. doi:https://doi.org/10.1038/nrd4334.

  3. Maniadakis, N., and A. Gray. 2000. The economic burden of back pain in the UK. Pain 84: 95–103.

    Article  CAS  PubMed  Google Scholar 

  4. Moulin, Dwight E., Alexander J. Clark, Mark Speechley, and Patricia K. Morley-Forster. 2002. Chronic pain in Canada--prevalence, treatment, impact and the role of opioid analgesia. Pain Research & Management 7: 179–184.

    Article  Google Scholar 

  5. Ji, Ru-rong, Alexander Chamessian, and Yu-qiu Zhang. 2016. Pain regulation by non-neuronal cells and inflammation. Science 354: 572–577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Manson, Stephanie C., Ruth E. Brown, Annamaria Cerulli, and Carlos Fernandez Vidaurre. 2009. The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use. Respiratory Medicine 103. Elsevier Ltd: 975–994. doi:https://doi.org/10.1016/j.rmed.2009.01.003.

  7. Süleyman, Halis, Berna Demircan, and Yalçin Karagöz. 2007. Anti-inflammatory and side effects of cyclooxygenase inhibitors. Pharmacological reports : PR 59: 247–258.

    PubMed  Google Scholar 

  8. Tapping, Richard I., and Peter S. Tobias. 2003. Mycobacterial lipoarabinomannan mediates physical interactions between TLR1 and TLR2 to induce signaling. Journal of Endotoxin Research 9: 264–268. https://doi.org/10.1179/096805103225001477.

    Article  CAS  PubMed  Google Scholar 

  9. Means, T.K., B.W. Jones, A.B. Schromm, B.A. Shurtleff, J.A. Smith, J. Keane, D.T. Golenbock, S.N. Vogel, and M.J. Fenton. 2001. Differential effects of a Toll-like receptor antagonist on Mycobacterium tuberculosis-induced macrophage responses. Journal of immunology (Baltimore, Md. : 1950) 166. American Association of Immunologists: 4074–82. doi:https://doi.org/10.4049/JIMMUNOL.166.6.4074.

  10. Yadav, Mahesh, and Jeffrey S Schorey. 2006. The beta-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria. Blood 108. American Society of Hematology: 3168–75. doi:https://doi.org/10.1182/blood-2006-05-024406.

  11. Ferwerda, Gerben, Stephen E. Girardin, Bart-Jan Kullberg, Lionel Le Bourhis, Dirk J. de Jong, Dennis M. L. Langenberg, Reinout van Crevel, et al. 2005. NOD2 and toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis. PLoS Pathogens 1. Public Library of Science: e34. doi:https://doi.org/10.1371/journal.ppat.0010034.

  12. Underhill, D.M., A. Ozinsky, K.D. Smith, and A. Aderem. 1999. Toll-like receptor-2 mediates mycobacteria-induced proinflammatory signaling in macrophages. Proceedings of the National Academy of Sciences of the United States of America 96. National Academy of Sciences: 14459–63.

  13. Kleinnijenhuis, Johanneke, Leo A. B. Joosten, Frank L. van de Veerdonk, Nigel Savage, Reinout van Crevel, Bart Jan Kullberg, Andre van der Ven, et al. 2009. Transcriptional and inflammasome-mediated pathways for the induction of IL-1β production by Mycobacterium tuberculosis. European Journal of Immunology 39. WILEY-VCH Verlag: 1914–1922. doi:https://doi.org/10.1002/eji.200839115.

  14. Maduka, U.P., M.V. Hamity, R.Y. Walder, S.R. White, Y. Li, and D.L. Hammond. 2016. Changes in the disposition of substance P in the rostral ventromedial medulla after inflammatory injury in the rat. Neuroscience 317: 1–11. https://doi.org/10.1016/j.neuroscience.2015.12.054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Raghavendra, Vasudeva, Flobert Y. Tanga, and Joyce A. Deleo. 2004. Complete Freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS. European Journal of Neuroscience 20: 467–473. https://doi.org/10.1111/j.1460-9568.2004.03514.x.

    Article  PubMed  Google Scholar 

  16. Yamamoto, A., H. Hara, S. Takaichi, J. Wakasugi, M. Tomikawa, S.G. Baker, B.I. Joffe, et al. 1988. Effect of probucol on macrophages, leading to regression of xanthomas and atheromatous vascular lesions. The American journal of cardiology 62. Elsevier: 31B–36B. doi:https://doi.org/10.1016/S0002-9149(88)80048-1.

  17. Bridges, A.B., N.A. Scott, and J.J.F. Belch. 1991. Probucol, a superoxide free radical scavenger in vitro. Atherosclerosis 89: 263–265. https://doi.org/10.1016/0021-9150(91)90068-E.

    Article  CAS  PubMed  Google Scholar 

  18. Aoki, M., T. Nata, R. Morishita, H. Matsushita, H. Nakagami, K. Yamamoto, K. Yamazaki, M. Nakabayashi, T. Ogihara, and Y. Kaneda. 2001. Endothelial apoptosis induced by oxidative stress through activation of NF-κB: Antiapoptotic effect of antioxidant agents on endothelial cells. Hypertension 38: 48–55. https://doi.org/10.1161/01.HYP.38.1.48.

    Article  CAS  PubMed  Google Scholar 

  19. Akeson, Ann L., Connie W. Woods, Laura B. Mosher, Craig E. Thomas, and Richard L. Jackson. 1991. Inhibition of IL-1b expression in THP-1 cells by probucol and tocopherol. Atherosclerosis 86: 261–270. https://doi.org/10.1016/0021-9150(91)90222-O.

    Article  CAS  PubMed  Google Scholar 

  20. Kaneko, M., J. Hayashi, I. Saito, and N. Miyasaka. 1996. Probucol downregulates E-selectin expression on cultured human vascular endothelial cells. Arteriosclerosis, Thrombosis, and Vascular Biology 16: 1047–1051. https://doi.org/10.1161/01.ATV.16.8.1047.

    Article  CAS  PubMed  Google Scholar 

  21. Liu, Ge-Xiu, Da-Ming Ou, Jun-Hua Liu, Hong-Lin Huang, and Duan-Fang Liao. 2000. Probucol inhibits lipid peroxidation of macrophage and affects its secretory properties. Acta Pharmacologica Sinica 21: 637–640.

    CAS  PubMed  Google Scholar 

  22. Zapolska-Downar, D., A. Zapolski-Downar, M. Markiewski, A. Ciechanowicz, M. Kaczmarczyk, and M. Naruszewicz. 2000. Selective inhibition by alpha-tocopherol of vascular cell adhesion molecule-1 expression in human vascular endothelial cells. Biochemical and Biophysical Research Communications 155: 609–615. https://doi.org/10.1006/bbrc.2000.3197.

    Article  CAS  Google Scholar 

  23. Zhang, M., J. Wang, J.H. Liu, S.J. Chen, B. Zhen, C.H. Wang, H. He, and C.X. Jiang. 2013. Effects of probucol on angiotensin II-induced BMP-2 expression in human umbilical vein endothelial cells. Molecular Medicine Reports 7: 177–182. https://doi.org/10.3892/mmr.2012.1145.

    Article  CAS  PubMed  Google Scholar 

  24. Al-Majed, Abdulhakeem a. 2011. Probucol attenuates oxidative stress, energy starvation, and nitric acid production following transient forebrain ischemia in the rat hippocampus. Oxidative Medicine and Cellular Longevity 2011: 1–8. https://doi.org/10.1155/2011/471590.

    Article  CAS  Google Scholar 

  25. Li, S., J. Liang, M. Niimi, A. Bilal Waqar, D. Kang, T. Koike, Y. Wang, M. Shiomi, and J. Fan. 2014. Probucol suppresses macrophage infiltration and MMP expression in atherosclerotic plaques of WHHL rabbits. Journal of Atherosclerosis and Thrombosis 21: 648–658. https://doi.org/10.5551/jat.21600.

    Article  CAS  PubMed  Google Scholar 

  26. Li, Tingting, Wenqiang Chen, Fengshuang An, Hongbo Tian, Jianning Zhang, Jie Peng, Yun Zhang, and Yuan Guo. 2011. Probucol attenuates inflammation and increases stability of vulnerable atherosclerotic plaques in rabbits. The Tohoku Journal of Experimental Medicine 225: 23–34. https://doi.org/10.1620/tjem.225.23.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang, Xia, Zhongzhuan Li, Dongfang Liu, Xin Xu, Wei Shen, and Zhechuan Mei. 2009. Effects of probucol on hepatic tumor necrosis factor-alpha, interleukin-6 and adiponectin receptor-2 expression in diabetic rats. Journal of Gastroenterology and Hepatology 24: 1058–1063. https://doi.org/10.1111/j.1440-1746.2008.05719.x.

    Article  CAS  PubMed  Google Scholar 

  28. Zucoloto, Amanda Z., Marília F. Manchope, Larrisa Staurengo-Ferrari, José C. Alves-Filho, Thiago M. Cunha, Maísa M. Antunes, Gustavo B. Menezes, Fernando Q. Cunha, Rubia Casagrande, and Waldiceu A. Verri. 2017. Probucol attenuates overt pain-like behavior and carrageenan-induced inflammatory hyperalgesia and leukocyte recruitment by inhibiting NF-кB activation and cytokine production without antioxidant effects. Inflammation Research 66: 591–602. https://doi.org/10.1007/s00011-017-1040-8.

    Article  CAS  PubMed  Google Scholar 

  29. Zucoloto, Amanda Z., Marília F. Manchope, Larissa Staurengo-Ferrari, Felipe A. Pinho-Ribeiro, Ana C. Zarpelon, André L.L. Saraiva, Nerry Tatiana Cecílio, José C. Alves-Filho, Thiago M. Cunha, Gustavo B. Menezes, Fernando Q. Cunha, Rubia Casagrande, and Waldiceu A. Verri Jr. 2017. Probucol attenuates lipopolysaccharide-induced leukocyte recruitment and inflammatory hyperalgesia: Effect on NF-кB activation and cytokine production. European Journal of Pharmacology 809: 52–63. https://doi.org/10.1016/j.ejphar.2017.05.016.

    Article  CAS  PubMed  Google Scholar 

  30. Mizokami, Sandra S., Nilton S. Arakawa, Sergio R. Ambrosio, Ana C. Zarpelon, Rubia Casagrande, Thiago M. Cunha, Sergio H. Ferreira, Fernando Q. Cunha, and Waldiceu A. Verri. 2012. Kaurenoic acid from Sphagneticola trilobata inhibits inflammatory pain: Effect on cytokine production and activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway. Journal of Natural Products 75: 896–904. https://doi.org/10.1021/np200989t.

    Article  CAS  PubMed  Google Scholar 

  31. Navarro, Suelen A., Karla G.G. Serafim, Sandra S. Mizokami, Miriam S.N. Hohmann, Rubia Casagrande, and Waldiceu A.Jr. Verri. 2013. Analgesic activity of piracetam: Effect on cytokine production and oxidative stress. Pharmacology Biochemistry and Behavior 105: 183–192. https://doi.org/10.1016/j.pbb.2013.02.018.

    Article  CAS  Google Scholar 

  32. Cunha, T.M., W.A. Jr Verri, G.G. Vivancos, I.F. Moreira, S. Reis, C.A. Parada, Fernando Q. Cunha, and S.H. Fereira. 2004. An electronic pressure-meter nociception paw test for rats. Brazilian Journal of Medical and Biological Research 37: 401–407. https://doi.org/10.1590/S0100-879X2004000300018.

    Article  CAS  PubMed  Google Scholar 

  33. Kuraishi, Y., Y. Harada, S. Aratani, M. Satoh, and H. Takagi. 1983. Separate involvement of the spinal noradrenergic and serotonergic systems in morphine analgesia: The differences in mechanical and thermal algesic tests. Brain Research 273: 245–252. https://doi.org/10.1016/0006-8993(83)90849-1.

    Article  CAS  PubMed  Google Scholar 

  34. Bradley, P., and D. Christensen. 2016. Cellular and extracellular Myeloperoxidade in pyogenic inflammation. Blood 60: 618–623.

    Google Scholar 

  35. Rossaneis, Ana C., Daniela T. Longhi-Balbinot, Mariana M. Bertozzi, Victor Fattori, Carina Z. Segato-Vendrameto, Stephanie Badaro-Garcia, Tiago H. Zaninelli, Larissa Staurengo-Ferrari, Sergio M. Borghi, Thacyana T. Carvalho, Allan J. C. Bussmann, Florêncio S. Gouveia Jr, Luiz G. F. Lopes, Rubia Casagrande, Waldiceu A. Verri Jr 2019. [Ru(bpy)2(NO)SO3](PF6), a nitric oxide donating ruthenium complex, reduces gout arthritis in mice. Frontiers in Pharmacology 10. Frontiers: 229. doi:https://doi.org/10.3389/FPHAR.2019.00229.

  36. Zarpelon, Ana C., Francielle C. Rodrigues, Alexandre H. Lopes, Guilherme R. Souza, Thacyana T. Carvalho, Larissa G. Pinto, Xu Damo, et al. 2016. Spinal cord oligodendrocyte-derived alarmin IL-33 mediates neuropathic pain. FASEB Journal 30: 54–65. https://doi.org/10.1096/fj.14-267146.

    Article  CAS  PubMed  Google Scholar 

  37. Hohmann, Miriam S.N., Renato D.R. Cardoso, Felipe A. Pinho-Ribeiro, Jefferson Crespigio, Thiago M. Cunha, José C. Alves-Filho, Rosiane V. da Silva, et al. 2013. 5-Lipoxygenase deficiency reduces acetaminophen-induced hepatotoxicity and lethality. BioMed research international 2013. Hindawi Publishing Corporation: 627046. doi:https://doi.org/10.1155/2013/627046.

  38. Curtis, R. Mason, and Marco L.A. Sivilotti. 2015. A descriptive analysis of aspartate and alanine aminotransferase rise and fall following acetaminophen overdose. Clinical Toxicology 53: 849–855. https://doi.org/10.3109/15563650.2015.1077968.

    Article  CAS  PubMed  Google Scholar 

  39. Fracasso, M.E., L. Cuzzolin, P. Del Soldato, R. Leone, G.P. Velo, and G. Benoni. 1987. Multisystem toxicity of indomethacin: Effects on kidney, liver and intestine in the rat. Agents and Actions 22: 310–313.

    Article  CAS  PubMed  Google Scholar 

  40. Syed, Nawazish-I-Husain, Farnaz Zehra, Amir Ali-Rizvi Syed, Sabiha Karim, and Farrakh Zia Khan. 2012. Comparing the effects of salts of diclofenac and alminoprofen with aspirin on serum electrolytes, creatinine and urea levels in rabbits. Pakistan Journal of Pharmaceutical Sciences 25: 777–782.

    CAS  PubMed  Google Scholar 

  41. Cunha, Thiago M., W.A. Jr Verri, Ieda R. Schivo, Marcelo H. Napimoga, Carlos a Parada, Stephen Poole, Mauro M. Teixeira, Sergio H. Ferreira, and Fernando Q. Cunha. 2008. Crucial role of neutrophils in the development of mechanical inflammatory hypernociception. Journal of Leukocyte Biology 83: 824–832. https://doi.org/10.1189/jlb.0907654.

    Article  CAS  PubMed  Google Scholar 

  42. Hartung, Jane E., Olivia Eskew, Terrence Wong, Inna E. Tchivileva, Folabomi A. Oladosu, Sandra C. O’Buckley, and Andrea G. Nackley. 2015. Nuclear factor-kappa B regulates pain and COMT expression in a rodent model of inflammation. Brain, Behavior, and Immunity 50: 196–202. https://doi.org/10.1016/j.bbi.2015.07.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhu, Ming Di, Lin Xia Zhao, Xiao Tian Wang, Yong Jing Gao, and Zhi Jun Zhang. 2014. Ligustilide inhibits microglia-mediated proinflammatory cytokines production and inflammatory pain. Brain Research Bulletin 109. Elsevier Inc.: 54–60. doi:https://doi.org/10.1016/j.brainresbull.2014.10.002.

  44. Jung, Yeon Suk, Jung Hwa Park, Hyunha Kim, So Young Kim, Ji Young Hwang, Ki Whan Hong, Sun Sik Bae, Byung Tae Choi, Sae-Won Lee, and Hwa Kyoung Shin. 2016. Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice. Acta Pharmacologica Sinica 37. Nature Publishing Group: 1031–44. doi:https://doi.org/10.1038/aps.2016.51.

  45. Xu, Fei, Youhan Li, Shuo Li, Yunqing Ma, Ning Zhao, Yong Liu, Niansong Qian, Hong Zho, and Yu Li. 2014. Complete Freund’s adjuvant-induced acute inflammatory pain could be attenuated by triptolide via inhibiting spinal glia activation in rats. The Journal of Surgical Research 188. Elsevier: 174–82. doi:https://doi.org/10.1016/j.jss.2013.11.1087.

  46. Sun, Shukai, Yue Yin, Xin Yin, Fale Cao, Daoshu Luo, Ting Zhang, Yunqing Li, and Longxing Ni. 2012. Anti-nociceptive effects of Tanshinone IIA (TIIA) in a rat model of complete Freund’s adjuvant (CFA)-induced inflammatory pain. Brain Research Bulletin 88: 581–588. https://doi.org/10.1016/j.brainresbull.2012.06.002.

    Article  CAS  PubMed  Google Scholar 

  47. Reiber, H., A.J. Suckling, and M.G. Rumsby. 1984. The effect of Freund’s adjuvants on blood-cerebrospinal fluid barrier permeability. Journal of the Neurological Sciences 63: 55–61.

    Article  CAS  PubMed  Google Scholar 

  48. Samad, T.A., K.A. Moore, A. Sapirstein, S. Billet, A. Allchorne, S. Poole, J.V. Bonventre, and C.J. Woolf. 2001. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410: 471–475. https://doi.org/10.1038/35068566.

    Article  CAS  PubMed  Google Scholar 

  49. Binshtok, A.M., H. Wang, and K. Zimmermann. 2008. Nociceptors are interleukin-1ßSensors. The Journal of Neuroscience 28: 14062–14073. https://doi.org/10.1523/JNEUROSCI.3795-08.2008.Nociceptors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cunha, T.M., W.A. Jr Verri, J.S. Silva, S. Poole, F.Q. Cunha, and S.H. Ferreira. 2005. A cascade of cytokines mediates mechanical inflammatory hypernociception in mice. Proceedings of the National Academy of Sciences of the United States of America 102: 1755–1760. https://doi.org/10.1073/pnas.0409225102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jin, X., W. Robert, and I.V. Gereau. 2006. Acute p38-mediated modulation of Tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-a. Journal of Neuroscience 26: 246–255. https://doi.org/10.1523/JNEUROSCI.3858-05.2006.

    Article  CAS  PubMed  Google Scholar 

  52. Vazquez, Enrique, Jan Kahlenbach, Gisela Segond von Banchet, Christian König, Hans-Georg Schaible, and Andrea Ebersberger. 2012. Spinal interleukin-6 is an amplifier of arthritic pain in the rat. Arthritis and Rheumatism 64: 2233–2242. https://doi.org/10.1002/art.34384.

    Article  CAS  PubMed  Google Scholar 

  53. Colle, Dirleise, Danúbia Bonfanti Santos, Eduardo Luiz Gasnhar Moreira, Juliana Montagna Hartwig, Alessandra Antunes dos Santos, Luciana Teixeira Zimmermann, Mariana Appel Hort, and Marcelo Farina. 2013. Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats. PLoS One 8: e67658. https://doi.org/10.1371/journal.pone.0067658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Siveski-Iliskovic, N., N. Kaul, and P.K. Singal. 1994. Probucol promotes endogenous antioxidants and provides protection against adriamycin-induced cardiomyopathy in rats. Circulation 89: 2829–2835. https://doi.org/10.1161/01.CIR.89.6.2829.

    Article  CAS  PubMed  Google Scholar 

  55. Chang, Weng Cheng, Chia Hsin Chen, Ming Fen Lee, Ted Chang, and Ya Mei Yu. 2010. Chlorogenic acid attenuates adhesion molecules upregulation in IL-1b-treated endothelial cells. European Journal of Nutrition 49: 267–275. https://doi.org/10.1007/s00394-009-0083-1.

    Article  CAS  PubMed  Google Scholar 

  56. Ghosh, Sankar, and Matthew S. Hayden. 2008. New regulators of NF-kB in inflammation. Nature Reviews Immunology 8: 837–848. https://doi.org/10.1038/nri2423.

    Article  CAS  PubMed  Google Scholar 

  57. Cao, S., X. Zhang, Justin P. Edwards, and David M. Mosser. 2006. NF-kB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages. Journal of Biological Chemistry 281: 26041–26050. https://doi.org/10.1074/jbc.M602222200.

    Article  CAS  PubMed  Google Scholar 

  58. McLeod, A.L., J.E. Krause, A.C. Cuello, and A. Ribeiro-da-Silva. 1998. Preferential synaptic relationships between substance P-immunoreactive boutons and neurokinin 1 receptor sites in the rat spinal cord. Proceedings of the National Academy of Sciences 95: 15775–15780. https://doi.org/10.1073/pnas.95.26.15775.

    Article  CAS  Google Scholar 

  59. Thomson, Lisa M., Gregory W. Terman, Jinsong Zeng, Janet Lowe, Charles Chavkin, Sam M. Hermes, Deborah M. Hegarty, and Sue A. Aicher. 2008. Decreased substance P and NK1 receptor immunoreactivity and function in the spinal cord dorsal horn of morphine-treated neonatal rats. The Journal of Pain 9: 11–19. https://doi.org/10.1016/j.jpain.2007.07.008.

    Article  CAS  PubMed  Google Scholar 

  60. Taylor, B.K., W. Fu, K.E. Kuphal, C.-O. Stiller, M.K. Winter, W. Chen, G.F. Corder, J.H. Urban, K.E. McCarson, and J.C. Marvizon. 2014. Inflammation enhances Y1 receptor signaling, neuropeptide Y-mediated inhibition of hyperalgesia, and substance P release from primary afferent neurons. Neuroscience 256: 178–194. https://doi.org/10.1016/j.neuroscience.2013.10.054.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank the technical support of Maria Rosana F. de Paula.

Funding

Conselho Nacional do Desenvolvimento Científico e Tecnológico (CNPq), Coordenação do Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Programa de Apoio a Grupos de Excelência (PRONEX) grant supported by SETI/Araucária Foundation, MCTI/CNPq, and Parana State Government (agreement 014/2017, protocol 46.843).

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Authors and Affiliations

  1. Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Brazil

    Amanda Z. Zucoloto, Marília F. Manchope, Sergio M. Borghi, Telma S. dos Santos, Victor Fattori, Stephanie Badaro-Garcia & Waldiceu A. Verri Jr

  2. Snyder Institute for Chronic Diseases, University of Calgary, HRIC 4C51, 3230 Hospital Dr NW, Calgary, AB, T2N 4N1, Canada

    Amanda Z. Zucoloto

  3. Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, HRIC 4C51, 3230 Hospital Dr NW, Calgary, AB, T2N 4N1, Canada

    Amanda Z. Zucoloto

  4. Departamento de Bioquímica e Biotecnologia, Centro de Ciências Exatas, Universidade Estadual de Londrina, Londrina, Brazil

    Doumit Camilios-Neto

  5. Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Estadual de Londrina, Londrina, Brazil

    Rubia Casagrande

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Zucoloto, A.Z., Manchope, M.F., Borghi, S.M. et al. Probucol Ameliorates Complete Freund’s Adjuvant-Induced Hyperalgesia by Targeting Peripheral and Spinal Cord Inflammation. Inflammation 42, 1474–1490 (2019). https://doi.org/10.1007/s10753-019-01011-3

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