Journal of Natural Medicines

, Volume 73, Issue 1, pp 217–225 | Cite as

The analgesic effect and possible mechanisms by which koumine alters type II collagen-induced arthritis in rats

  • Gui-Lin Jin
  • Jian Yang
  • Wan-Qing Chen
  • Jie Wang
  • Hong-Qiang Qiu
  • Ying Xu
  • Chang-Xi YuEmail author


Gelsemium elegans Benth. is a toxic plant that has been used as an ancient Chinese herbal remedy for rheumatoid arthritis (RA) and nervous pain, spasticity, skin ulcers, and cancers. Koumine, one of its representative alkaloids, shows numerous promising pharmacological activities, including anti-inflammatory and analgesic activities. Here, we investigated the analgesic effect of koumine on the collagen-induced arthritis (CIA) rat model of RA and explored the potential pharmacological mechanisms underlying the analgesia. In the CIA rats, repeated koumine treatments significantly reduced pain compared to controls and attenuated the collagen-induced increase in levels of glial fibrillary acidic protein (GFAP) and the pro-inflammatory cytokines tumour necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Cultured astrocytes showed reduced astrocyte reactivation and decreased production of both tested cytokines. Based on our results, koumine exerted both analgesic and anti-inflammatory effects on the CIA rat model that were apparently mediated by inhibiting astrocyte reactivation and pro-inflammatory cytokine production.


Koumine Inflammation Pain Astrocyte Rheumatoid arthritis Rats 



This work was supported by grants from the National Natural Science Foundation of China (Nos. 81603094 and 81773716), the Natural Science Foundation of Fujian Province of China (Nos. 2016J05191 and 2016J01367), and the Joint Funds for the Innovation of Science and Technology, Fujian province (Grant Nos. 2016Y9049 and 2016Y9058).

Compliance with ethical standards

Ethical approval

The study protocols complied with the guidelines of the Ethics Committee of Fujian Medical University and conformed to the NIH Guide for the Care and Use of Laboratory Animals (Authorization number: 2016-13).

Conflicts of interest

The authors have no conflicts of interest to declare.


  1. 1.
    McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205–2219CrossRefGoogle Scholar
  2. 2.
    Bas DB, Su J, Wigerblad G, Svensson CI (2016) Pain in rheumatoid arthritis: models and mechanisms. Pain Manag 6:265–284CrossRefGoogle Scholar
  3. 3.
    Calabro A, Caterino AL, Elefante E, Valentini V, Vitale A, Talarico R, Cantarini L, Frediani B (2016) One year in review 2016: novelties in the treatment of rheumatoid arthritis. Clin Exp Rheumatol 34:357–372Google Scholar
  4. 4.
    Walsh DA, McWilliams DF (2014) Mechanisms, impact and management of pain in rheumatoid arthritis. Nat Rev Rheumatol 10:581–592CrossRefGoogle Scholar
  5. 5.
    Meeus M, Vervisch S, De Clerck LS, Moorkens G, Hans G, Nijs J (2012) Central sensitization in patients with rheumatoid arthritis: a systematic literature review. Semin Arthritis Rheu 41:556–567CrossRefGoogle Scholar
  6. 6.
    Woolf CJ (2018) Pain amplification—a perspective on the how, why, when, and where of central sensitization. J Appl Biobehav Res 23:e12124CrossRefGoogle Scholar
  7. 7.
    Nieto FR, Clark AK, Grist J, Hathway GJ, Chapman V, Malcangio M (2016) Neuron-immune mechanisms contribute to pain in early stages of arthritis. J Neuroinflammation 13:96CrossRefGoogle Scholar
  8. 8.
    Bas DB, Su J, Sandor K, Agalave NM, Lundberg J, Codeluppi S, Baharpoor A, Nandakumar KS, Holmdahl R, Svensson CI (2012) Collagen antibody-induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency. Arthritis Rheum 64:3886–3896CrossRefGoogle Scholar
  9. 9.
    Carr FB, Geranton SM, Hunt SP (2014) Descending controls modulate inflammatory joint pain and regulate CXC chemokine and iNOS expression in the dorsal horn. Mol Pain 10:39CrossRefGoogle Scholar
  10. 10.
    Salaffi F, Giacobazzi G, Di Carlo M (2018) (2018) Chronic pain in inflammatory arthritis: mechanisms, metrology, and emerging targets—a focus on the JAK-STAT pathway. Pain Res Manage 3:8564215Google Scholar
  11. 11.
    Inglis JJ, Notley CA, Essex D, Wilson AW, Feldmann M, Anand P, Williams R (2007) Collagen-induced arthritis as a model of hyperalgesia: functional and cellular analysis of the analgesic actions of tumor necrosis factor blockade. Arthritis Rheum 56:4015–4023CrossRefGoogle Scholar
  12. 12.
    Christianson CA, Dumlao DS, Stokes JA, Dennis EA, Svensson CI, Corr M, Yaksh TL (2011) Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-transferred arthritis. Pain 152:2881–2891CrossRefGoogle Scholar
  13. 13.
    Schaible HG, von Banchet GS, Boettger MK, Brauer R, Gajda M, Richter F, Hensellek S, Brenn D, Natura G (2010) The role of proinflammatory cytokines in the generation and maintenance of joint pain. Ann N Y Acad Sci 1193:60–69CrossRefGoogle Scholar
  14. 14.
    Ji RR, Chamessian A, Zhang YQ (2016) Pain regulation by non-neuronal cells and inflammation. Science 354:572–577CrossRefGoogle Scholar
  15. 15.
    Hansen RR, Malcangio M (2013) Astrocytes—multitaskers in chronic pain. Eur J Pharmacol 716:120–128CrossRefGoogle Scholar
  16. 16.
    Gao YJ, Ji RR (2010) Targeting astrocyte signaling for chronic pain. Neurotherapeutics 7:482–493CrossRefGoogle Scholar
  17. 17.
    Ji RR, Xu ZZ, Gao YJ (2014) Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discovery 13:533–548CrossRefGoogle Scholar
  18. 18.
    Jin G-L, Su Y-P, Liu M, Xu Y, Yang J, Liao K-J, Yu C-X (2014) Medicinal plants of the genus Gelsemium (Gelsemiaceae, Gentianales)—a review of their phytochemistry, pharmacology, toxicology and traditional use. J Ethnopharmacol 152:33–52CrossRefGoogle Scholar
  19. 19.
    Ghorbani A, Langenberger G, Feng L, Sauerborn J (2011) Ethnobotanical study of medicinal plants utilised by Hani ethnicity in Naban River Watershed National Nature Reserve, Yunnan, China. J Ethnopharmacol 134:651–667CrossRefGoogle Scholar
  20. 20.
    Rujjanawate C, Kanjanapothi D, Panthong A (2003) Pharmacological effect and toxicity of alkaloids from Gelsemium elegans Benth. J Ethnopharmacol 89:91–95CrossRefGoogle Scholar
  21. 21.
    Xu Y, Qiu H-Q, Liu H, Liu M, Huang Z-Y, Yang J, Su Y-P, Yu C-X (2012) Effects of koumine, an alkaloid of Gelsemium elegans Benth., on inflammatory and neuropathic pain models and possible mechanism with allopregnanolone. Pharmacol Biochem Behav 101:504–514CrossRefGoogle Scholar
  22. 22.
    Chen CJ, Zhong ZF, Xin ZM, Hong LH, Su YP, Yu CX (2017) Koumine exhibits anxiolytic properties without inducing adverse neurological effects on functional observation battery, open-field and Vogel conflict tests in rodents. J Nat Med 71:397–408CrossRefGoogle Scholar
  23. 23.
    Xiong BJ, Xu Y, Jin GL, Liu M, Yang J, Yu CX (2017) Analgesic effects and pharmacologic mechanisms of theGelsemiumalkaloid koumine on a rat model of postoperative pain. Sci Rep 7:14269CrossRefGoogle Scholar
  24. 24.
    Jian Y, Cai HD, Zeng YL, Chen ZH, Fang MH, Su YP, Huang HH, Ying X, Yu CX (2016) Effects of koumine on adjuvant- and collagen-induced arthritis in rats. J Nat Prod 79:2635–2643CrossRefGoogle Scholar
  25. 25.
    Su Y-P, Shen J, Xu Y, Zheng M, Yu C-X (2011) Preparative separation of alkaloids from Gelsemium elegans Benth. using pH-zone-refining counter-current chromatography. J Chromatogr A 1218:3695–3698CrossRefGoogle Scholar
  26. 26.
    Mitrirattanakul S, Ramakul N, Guerrero AV, Matsuka Y, Ono T, Iwase H, Mackie K, Faull KF, Spigelman I (2006) Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain. Pain 126:102–114CrossRefGoogle Scholar
  27. 27.
    Woolf CJ (2011) Central sensitization: implications for the diagnosis and treatment of pain. Pain 152:S2–15CrossRefGoogle Scholar
  28. 28.
    Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10:23–36CrossRefGoogle Scholar
  29. 29.
    Agalave NM, Larsson M, Abdelmoaty S, Su J, Baharpoor A, Lundback P, Palmblad K, Andersson U, Harris H, Svensson CI (2014) Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis. Pain 155:1802–1813CrossRefGoogle Scholar
  30. 30.
    Clark AK, Grist J, Al-Kashi A, Perretti M, Malcangio M (2012) Spinal cathepsin S and fractalkine contribute to chronic pain in the collagen-induced arthritis model. Arthritis Rheum 64:2038–2047CrossRefGoogle Scholar
  31. 31.
    Sun S, Cao H, Han M, Li TT, Pan HL, Zhao ZQ, Zhang YQ (2007) New evidence for the involvement of spinal fractalkine receptor in pain facilitation and spinal glial activation in rat model of monoarthritis. Pain 129:64–75CrossRefGoogle Scholar
  32. 32.
    Svensson M, Eriksson NP, Aldskogius H (1993) Evidence for activation of astrocytes via reactive microglial cells following hypoglossal nerve transection. J Neurosci Res 35:373–381CrossRefGoogle Scholar
  33. 33.
    Tanga FY, Raghavendra V, DeLeo JA (2004) Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochem Int 45:397–407CrossRefGoogle Scholar
  34. 34.
    Zhang J, De Koninck Y (2006) Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. J Neurochem 97:772–783CrossRefGoogle Scholar
  35. 35.
    Bao L, Zhu Y, Elhassan AM, Wu Q, Xiao B, Zhu J, Lindgren JU (2001) Adjuvant-induced arthritis: IL-1β, IL-6 and TNF-α are up-regulated in the spinal cord. NeuroReport 12:3905–3908CrossRefGoogle Scholar
  36. 36.
    Gruber-Schoffnegger D, Drdla-Schutting R, Hönigsperger C, Wunderbaldinger G, Gassner M, Sandkühler J (2013) Induction of thermal hyperalgesia and synaptic long-term potentiation in the spinal cord lamina I by TNF-α and IL-1β is mediated by glial cells. J Neurosci 33:6540–6551CrossRefGoogle Scholar
  37. 37.
    Hess A, Axmann R, Rech J, Finzel S, Heindl C, Kreitz S, Sergeeva M, Saake M, Garcia M, Kollias G et al (2011) Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. Proc Natl Acad Sci USA 108:3731–3736CrossRefGoogle Scholar
  38. 38.
    Boettger MK, Weber K, Grossmann D, Gajda M, Bauer R, Bar KJ, Schulz S, Voss A, Geis C, Brauer R et al (2010) Spinal tumor necrosis factor alpha neutralization reduces peripheral inflammation and hyperalgesia and suppresses autonomic responses in experimental arthritis: a role for spinal tumor necrosis factor alpha during induction and maintenance of peripheral inflammation. Arthritis Rheum 62:1308–1318CrossRefGoogle Scholar
  39. 39.
    Berta T, Liu YC, Xu ZZ, Ji RR (2013) Tissue plasminogen activator contributes to morphine tolerance and induces mechanical allodynia via astrocytic IL-1β and ERK signaling in the spinal cord of mice. Neuroscience 247:376–385CrossRefGoogle Scholar
  40. 40.
    Constandil L, Hernandez A, Pelissier T, Arriagada O, Espinoza K, Burgos H, Laurido C (2009) Effect of interleukin-1beta on spinal cord nociceptive transmission of normal and monoarthritic rats after disruption of glial function. Arthritis Res Ther 11:R105CrossRefGoogle Scholar
  41. 41.
    Marchand F, Perretti M, McMahon SB (2005) Role of the immune system in chronic pain. Nat Rev Neurosci 6:521–532CrossRefGoogle Scholar
  42. 42.
    Binshtok AM, Wang H, Zimmermann K, Amaya F, Vardeh D, Shi L, Brenner GJ, Ji RR, Bean BP, Woolf CJ et al (2008) Nociceptors are interleukin-1beta sensors. J Neurosci 28:14062–14073CrossRefGoogle Scholar
  43. 43.
    Kawasaki Y, Zhang L, Cheng JK, Ji RR (2008) Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci 28:5189–5194CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Pharmacognosy and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Gui-Lin Jin
    • 1
    • 2
  • Jian Yang
    • 1
    • 2
  • Wan-Qing Chen
    • 1
  • Jie Wang
    • 1
  • Hong-Qiang Qiu
    • 1
  • Ying Xu
    • 1
    • 2
  • Chang-Xi Yu
    • 1
    • 2
    Email author
  1. 1.Department of Pharmacology, College of PharmacyFujian Medical UniversityFuzhouPeople’s Republic of China
  2. 2.Fujian Key Laboratory of Natural Medicine Pharmacology, College of PharmacyFujian Medical UniversityFuzhouPeople’s Republic of China

Personalised recommendations