Advertisement

Psychopharmacology

, Volume 235, Issue 9, pp 2559–2571 | Cite as

Lappaconitine, a C18-diterpenoid alkaloid, exhibits antihypersensitivity in chronic pain through stimulation of spinal dynorphin A expression

  • Ming-Li Sun
  • Jun-Ping Ao
  • Yi-Rui Wang
  • Qian Huang
  • Teng-Fei Li
  • Xin-Yan Li
  • Yong-Xiang Wang
Original Investigation
  • 96 Downloads

Abstract

Lappaconitine is a representative C18-diterpenoid alkaloid extracted from Aconitum sinomontanum Nakai and has been prescribed as a pain relief medicine in China for more than 30 years. This study evaluated its antihypersensitivity activity in the rat models of neuropathic and cancer pains and explored its underlying mechanisms. Subcutaneous injection of cumulative doses of lappaconitine produced dose-dependent mechanical antiallodynia and thermal antihyperalgesia in spinal nerve ligation-induced neuropathic rats. The cumulative dose–response analysis exhibited their Emax values of 53.3 and 58.3% MPE, and ED50 values of 1.1 and 1.6 mg/kg. Single intrathecal lappaconitine dose in neuropathy also dose- and time-dependently blocked mechanical allodynia, with an Emax of 66.1% MPE and an ED50 of 0.8 μg. Its multiple twice-daily intrathecal administration over 7 days did not induce mechanical antiallodynic tolerance. Subcutaneous cumulative doses of lappaconitine also produced dose-dependent blockade of mechanical allodynia in the rat bone cancer pain model induced by tibia implantation of cancer cells, with the Emax of 57.9% MPE and ED50 of 2.0 mg/kg. Furthermore, lappaconitine treatment stimulated spinal dynorphin A expression in neuropathic rats, and in primary cultures of microglia but not neurons or astrocytes. Intrathecal pretreatment with the specific microglia depletor liposome-encapsulated clodronate, dynorphin A antibody, and κ-opioid receptor antagonist GNTI totally suppressed intrathecal and subcutaneous lappaconitine-induced mechanical antiallodynia. This study suggests that lappaconitine exhibits antinociception through directly stimulating spinal microglial dynorphin A expression.

Graphical Abstract

Keywords

Lappaconitine Neuropathic pain Bone cancer pain Dynorphin a Spinal microglia 

Abbreviations

POMC

proopiomelanocortin

GNTI

5′-Guanidinonaltrindole

TNF-α

Tumor necrosis factor-α

IL-6

Interleukin-6

IL-1β

Interleukin-1β

LPS

Lipopolysaccharides

GAPDH

glyceraldehyde-3-phosphate dehydrogenase

GsPCR

Gs-protein-coupled receptor

MAPK

Mitogen-activated protein kinase

ANOVA

Analysis of variance

% MPE

% maximal possible effect

Emax

Maximum effect

ED50 or EC50

Half-effective dose or half-effective concentration

Notes

Author contributions

Conceived and designed the experiments: YXW and MLS; performed the experiments: MLS, JPA, YRW, XYL, QH, and TFL; analyzed the data: YXW and MLS; and preparation of the paper: YXW and MLS.

Funding information

This study was supported in part by a grant from the National Natural Science Foundation of China (no. 81673403).

Compliance with ethical standards

Conflict of interest

The authors declare that there are no competing interests.

References

  1. Ameri A (1998) The effects of Aconitum alkaloids on the central nervous system. Prog Neurobiol 56:211–235CrossRefGoogle Scholar
  2. Bowersox SS, Gadbois T, Singh T, Pettus M, Wang YX, Luther RR (1996) Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX-111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain. J Pharmacol Exp Ther 279:1243–1249PubMedPubMedCentralGoogle Scholar
  3. Chavkin C (2013) Dynorphin—still an extraordinarily potent opioid peptide. Mol Pharmacol 83:729–736CrossRefGoogle Scholar
  4. Chen MG, Wang QH, Lin W (1996) Clinical study in epidural injection with lappaconitine compound for post-operative analgesia. Zhongguo Zhong Xi Yi Jie He Za Zhi 16:525–528PubMedPubMedCentralGoogle Scholar
  5. Dehghani F, Conrad A, Kohl A, Korf HW, Hailer NP (2004) Clodronate inhibits the secretion of proinflammatory cytokines and NO by isolated microglial cells and reduces the number of proliferating glial cells in excitotoxically injured organotypic hippocampal slice cultures. Exp Neurol 189:241–251CrossRefGoogle Scholar
  6. Drabek T, Janata A, Jackson EK, End B, Stezoski J, Vagni VA, Janesko-Feldman K, Wilson CD, van Rooijen N, Tisherman SA, Kochanek PM (2012) Microglial depletion using intrahippocampal injection of liposome-encapsulated clodronate in prolonged hypothermic cardiac arrest in rats. Resuscitation 83:517–526CrossRefGoogle Scholar
  7. Echeverry S, Shi XQ, Zhang J (2008) Characterization of cell proliferation in rat spinal cord following peripheral nerve injury and the relationship with neuropathic pain. Pain 135:37–47CrossRefGoogle Scholar
  8. Ellett JD, Atkinson C, Evans ZP, Amani Z, Balish E, Schmidt MG, van Rooijen N, Schnellmann RG, Chavin KD (2010) Murine Kupffer cells are protective in total hepatic ischemia/reperfusion injury with bowel congestion through IL-10. J Immunol 184:5849–5858CrossRefGoogle Scholar
  9. Fan H, Gong N, Li TF, Ma AN, Wu XY, Wang MW, Wang YX (2015) The non-peptide GLP-1 receptor agonist WB4-24 blocks inflammatory nociception by stimulating beta-endorphin release from spinal microglia. Br J Pharmacol 172:64–79CrossRefGoogle Scholar
  10. Gong QA, Li M (2015) Effect of lappaconitine on postoperative pain and serum complement 3 and 4 levels of cancer patients undergoing rectum surgery. Zhongguo Zhong Xi Yi Jie He Za Zhi 35:668–672PubMedPubMedCentralGoogle Scholar
  11. Gong N, Fan H, Ma AN, Xiao Q, Wang YX (2014a) Geniposide and its iridoid analogs exhibit antinociception by acting at the spinal GLP-1 receptors. Neuropharmacology 84:31–45CrossRefGoogle Scholar
  12. Gong N, Xiao Q, Zhu B, Zhang CY, Wang YC, Fan H, Ma AN, Wang YX (2014b) Activation of spinal glucagon-like peptide-1 receptors specifically suppresses pain hypersensitivity. J Neurosci 34:5322–5334CrossRefGoogle Scholar
  13. Guo X, Tang XC (1990a) Effects of reserpine and 5-HT on analgesia induced by lappaconitine and N-deacetyllappaconitine. Zhongguo Yao Li Xue Bao 11:14–18PubMedPubMedCentralGoogle Scholar
  14. Guo X, Tang XC (1990b) Roles of periaqueductal gray and nucleus raphe magnus on analgesia induced by lappaconitine, N-deacetyllappaconitine and morphine. Zhongguo Yao Li Xue Bao 11:107–112PubMedPubMedCentralGoogle Scholar
  15. Guo T, Zhang Y, Zhao J, Zhu C, Feng N (2015) Nanostructured lipid carriers for percutaneous administration of alkaloids isolated from Aconitum sinomontanum. J Nanobiotechnology 13:47CrossRefGoogle Scholar
  16. Huang JL, Chen XL, Guo C, Wang YX (2012) Contributions of spinal D-amino acid oxidase to bone cancer pain. Amino Acids 43:1905–1918CrossRefGoogle Scholar
  17. Huang Q, Mao XF, Wu HY, Li TF, Sun ML, Liu H, Wang YX (2016) Bullatine A stimulates spinal microglial dynorphin A expression to produce anti-hypersensitivity in a variety of rat pain models. J Neuroinflammation 13:214CrossRefGoogle Scholar
  18. Huang Q, Sun ML, Chen Y, Li XY, Wang YX (2017a) Concurrent bullatine A enhances morphine antinociception and inhibits morphine antinociceptive tolerance by indirect activation of spinal kappa-opioid receptors. J Ethnopharmacol 196:151–159CrossRefGoogle Scholar
  19. Huang Q, Sun ML, Li TF, Wang YX (2017b) Research progress on mechanisms underlying aconitines analgesia. Acta Neuropharmacologica 7:38–49Google Scholar
  20. Inoue K (2006) The function of microglia through purinergic receptors: neuropathic pain and cytokine release. Pharmacol Ther 109:210–226CrossRefGoogle Scholar
  21. Jha MK, Jeon S, Suk K (2012) Glia as a link between neuroinflammation and neuropathic pain. Immune Netw 12:41–47CrossRefGoogle Scholar
  22. Kim SH, Chung JM (1992) An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50:355–363CrossRefGoogle Scholar
  23. Kohl A, Dehghani F, Korf HW, Hailer NP (2003) The bisphosphonate clodronate depletes microglial cells in excitotoxically injured organotypic hippocampal slice cultures. Exp Neurol 181:1–11CrossRefGoogle Scholar
  24. Laughlin TM, Larson AA, Wilcox GL (2001) Mechanisms of induction of persistent nociception by dynorphin. J Pharmacol Exp Ther 299:6–11PubMedPubMedCentralGoogle Scholar
  25. Leitl MD, Onvani S, Bowers MS, Cheng K, Rice KC, Carlezon WA Jr, Banks ML, Negus SS (2014) Pain-related depression of the mesolimbic dopamine system in rats: expression, blockade by analgesics, and role of endogenous kappa-opioids. Neuropsychopharmacology 39:614–624CrossRefGoogle Scholar
  26. Li TF, Fan H, Wang YX (2016a) Aconitum-derived bulleyaconitine A exhibits antihypersensitivity through direct stimulating dynorphin A expression in spinal microglia. J Pain 17:530–548CrossRefGoogle Scholar
  27. Li TF, Gong N, Wang YX (2016b) Ester hydrolysis differentially reduces aconitine-induced anti-hypersensitivity and acute neurotoxicity: involvement of spinal microglial dynorphin expression and implications for Aconitum processing. Front Pharmacol 7:367PubMedPubMedCentralGoogle Scholar
  28. Li TF, Wu HY, Wang YR, Li XY, Wang YX (2017) Molecular signaling underlying bulleyaconitine A (BAA)-induced microglial expression of prodynorphin. Sci Rep 7:45056CrossRefGoogle Scholar
  29. Lisboa SF, Gomes FV, Guimaraes FS, Campos AC (2016) Microglial cells as a link between cannabinoids and the immune hypothesis of psychiatric disorders. Front Neurol 7:5CrossRefGoogle Scholar
  30. Liu JH, Zhu YX, Tang XC (1987) Anti-inflammatory and analgesic activities of N-deacetyllappaconitine and lappaconitine. Zhongguo Yao Li Xue Bao 8:301–305PubMedPubMedCentralGoogle Scholar
  31. Lu JM, Gong N, Wang YC, Wang YX (2012) D-Amino acid oxidase-mediated increase in spinal hydrogen peroxide is mainly responsible for formalin-induced tonic pain. Br J Pharmacol 165:1941–1955CrossRefGoogle Scholar
  32. Ono M, Satoh T (1989) Pharmacological studies of lappaconitine. Occurrence of analgesic effect without opioid receptor. Res Commun Chem Pathol Pharmacol 63:13–25PubMedPubMedCentralGoogle Scholar
  33. Ono M, Satoh T (1992) Pharmacological studies on lappaconitine: possible interaction with endogenous noradrenergic and serotonergic pathways to induce antinociception. Jpn J Pharmacol 58:251–257CrossRefGoogle Scholar
  34. Ou S, Zhao YD, Xiao Z, Wen HZ, Cui J, Ruan HZ (2011) Effect of lappaconitine on neuropathic pain mediated by P2X3 receptor in rat dorsal root ganglion. Neurochem Int 58:564–573CrossRefGoogle Scholar
  35. Storkson RV, Kjorsvik A, Tjolsen A, Hole K (1996) Lumbar catheterization of the spinal subarachnoid space in the rat. J Neurosci Methods 65:167–172CrossRefGoogle Scholar
  36. Sun W, Wang Y, Zhang J, Yu K (2009) X-ray structure analysis of lappaconitine. Nat Prod Res 23:960–962CrossRefGoogle Scholar
  37. Tang XC, Zhu MY, Feng J, Wang YE (1983) Pharmacologic actions of lappaconitine hydrobromide. Yao Xue Xue Bao 18:579–584Google Scholar
  38. Van Rooijen N, Sanders A, Van den Berg TK (1996) Apoptosis of macrophages induced by liposome-mediated intracellular delivery of clodronate and propamidine. J Immunol Methods 193:93–99CrossRefGoogle Scholar
  39. Wang YX, Pang CC (1993) Functional integrity of the central and sympathetic nervous systems is a prerequisite for pressor and tachycardic effects of diphenyleneiodonium, a novel inhibitor of nitric oxide synthase. J Pharmacol Exp Ther 265:263–272Google Scholar
  40. Wang JL, Shen XL, Chen QH, Qi G, Wang W, Wang FP (2009a) Structure-analgesic activity relationship studies on the C (18)- and C (19)-diterpenoid alkaloids. Chem Pharm Bull (Tokyo) 57:801–807CrossRefGoogle Scholar
  41. Wang YZ, Xiao YQ, Zhang C, Sun XM (2009b) Study of analgesic and anti-inflammatory effects of lappaconitine gelata. J Tradit Chin Med 29:141–145CrossRefGoogle Scholar
  42. Wang YX, Mao XF, Li TF, Gong N, Zhang MZ (2017) Dezocine exhibits antihypersensitivity activities in neuropathy through spinal mu-opioid receptor activation and norepinephrine reuptake inhibition. Sci Rep 7:43137CrossRefGoogle Scholar
  43. Wang YR, Mao XF, Wu HY, Wang YX (2018) Liposome-encapsulated clodronate specifically depletes spinal microglia and reduces initial neuropathic pain. Biochem Biophys Res Commun 499:499–505CrossRefGoogle Scholar
  44. Wright SN (2001) Irreversible block of human heart (hH1) sodium channels by the plant alkaloid lappaconitine. Mol Pharmacol 59:183–192CrossRefGoogle Scholar
  45. Wu HY, Mao XF, Fan H, Wang YX (2017) p38beta mitogen-activated protein kinase signaling mediates exenatide-stimulated microglial beta-endorphin expression. Mol Pharmacol 91:451–463CrossRefGoogle Scholar
  46. Yuan CL, Wang XL (2012) Isolation of active substances and bioactivity of Aconitum sinomontanum Nakai. Nat Prod Res 26:2099–2102PubMedPubMedCentralGoogle Scholar
  47. Zhang JY, Gong N, Huang JL, Guo LC, Wang YX (2013) Gelsemine, a principal alkaloid from Gelsemium sempervirens Ait., exhibits potent and specific antinociception in chronic pain by acting at spinal alpha3 glycine receptors. Pain 154:2452–2462CrossRefGoogle Scholar
  48. Zhu B, Gong N, Fan H, Peng CS, Ding XJ, Jiang Y, Wang YX (2014) Lamiophlomis rotata, an orally available Tibetan herbal painkiller, specifically reduces pain hypersensitivity states through the activation of spinal glucagon-like peptide-1 receptors. Anesthesiology 121:835–851CrossRefGoogle Scholar
  49. Zhu XC, Ge CT, Wang P, Zhang JL, Yu YY, Fu CY (2015) Analgesic effects of lappaconitine in leukemia bone pain in a mouse model. PeerJ 3:e936CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.King’s LabShanghai Jiao Tong University School of PharmacyShanghaiChina
  2. 2.State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina

Personalised recommendations