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

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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.

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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

E max :

Maximum effect

ED50 or EC50 :

Half-effective dose or half-effective concentration

References

  • Ameri A (1998) The effects of Aconitum alkaloids on the central nervous system. Prog Neurobiol 56:211–235

    Article  CAS  PubMed  Google Scholar 

  • 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 279:1243–1249

    CAS  PubMed  Google Scholar 

  • Chavkin C (2013) Dynorphin—still an extraordinarily potent opioid peptide. Mol Pharmacol 83:729–736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 16:525–528

    CAS  PubMed  Google Scholar 

  • 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 189:241–251

    Article  CAS  PubMed  Google Scholar 

  • 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 83:517–526

    Article  CAS  PubMed  Google Scholar 

  • 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 135:37–47

    Article  CAS  PubMed  Google Scholar 

  • 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 184:5849–5858

    Article  CAS  PubMed  Google Scholar 

  • 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 172:64–79

    Article  CAS  PubMed  Google Scholar 

  • 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 35:668–672

    CAS  PubMed  Google Scholar 

  • 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 84:31–45

    Article  CAS  PubMed  Google Scholar 

  • 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 34:5322–5334

    Article  PubMed  PubMed Central  Google Scholar 

  • Guo X, Tang XC (1990a) Effects of reserpine and 5-HT on analgesia induced by lappaconitine and N-deacetyllappaconitine. Zhongguo Yao Li Xue Bao 11:14–18

    CAS  PubMed  Google Scholar 

  • 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 11:107–112

    CAS  PubMed  Google Scholar 

  • 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 13:47

    Article  PubMed  PubMed Central  Google Scholar 

  • Huang JL, Chen XL, Guo C, Wang YX (2012) Contributions of spinal D-amino acid oxidase to bone cancer pain. Amino Acids 43:1905–1918

    Article  CAS  PubMed  Google Scholar 

  • 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 13:214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 196:151–159

    Article  CAS  PubMed  Google Scholar 

  • Huang Q, Sun ML, Li TF, Wang YX (2017b) Research progress on mechanisms underlying aconitines analgesia. Acta Neuropharmacologica 7:38–49

    Google Scholar 

  • Inoue K (2006) The function of microglia through purinergic receptors: neuropathic pain and cytokine release. Pharmacol Ther 109:210–226

    Article  CAS  PubMed  Google Scholar 

  • Jha MK, Jeon S, Suk K (2012) Glia as a link between neuroinflammation and neuropathic pain. Immune Netw 12:41–47

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim SH, Chung JM (1992) An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50:355–363

    Article  CAS  Google Scholar 

  • Kohl A, Dehghani F, Korf HW, Hailer NP (2003) The bisphosphonate clodronate depletes microglial cells in excitotoxically injured organotypic hippocampal slice cultures. Exp Neurol 181:1–11

    Article  CAS  PubMed  Google Scholar 

  • Laughlin TM, Larson AA, Wilcox GL (2001) Mechanisms of induction of persistent nociception by dynorphin. J Pharmacol Exp Ther 299:6–11

    CAS  PubMed  Google Scholar 

  • 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 39:614–624

    Article  CAS  PubMed  Google Scholar 

  • Li TF, Fan H, Wang YX (2016a) Aconitum-derived bulleyaconitine A exhibits antihypersensitivity through direct stimulating dynorphin A expression in spinal microglia. J Pain 17:530–548

    Article  CAS  PubMed  Google Scholar 

  • 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 7:367

    PubMed  PubMed Central  Google Scholar 

  • Li TF, Wu HY, Wang YR, Li XY, Wang YX (2017) Molecular signaling underlying bulleyaconitine A (BAA)-induced microglial expression of prodynorphin. Sci Rep 7:45056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 7:5

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu JH, Zhu YX, Tang XC (1987) Anti-inflammatory and analgesic activities of N-deacetyllappaconitine and lappaconitine. Zhongguo Yao Li Xue Bao 8:301–305

    CAS  PubMed  Google Scholar 

  • 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 165:1941–1955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ono M, Satoh T (1989) Pharmacological studies of lappaconitine. Occurrence of analgesic effect without opioid receptor. Res Commun Chem Pathol Pharmacol 63:13–25

    CAS  PubMed  Google Scholar 

  • Ono M, Satoh T (1992) Pharmacological studies on lappaconitine: possible interaction with endogenous noradrenergic and serotonergic pathways to induce antinociception. Jpn J Pharmacol 58:251–257

    Article  CAS  PubMed  Google Scholar 

  • 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 58:564–573

    Article  CAS  PubMed  Google Scholar 

  • Storkson RV, Kjorsvik A, Tjolsen A, Hole K (1996) Lumbar catheterization of the spinal subarachnoid space in the rat. J Neurosci Methods 65:167–172

    Article  CAS  PubMed  Google Scholar 

  • Sun W, Wang Y, Zhang J, Yu K (2009) X-ray structure analysis of lappaconitine. Nat Prod Res 23:960–962

    Article  CAS  PubMed  Google Scholar 

  • Tang XC, Zhu MY, Feng J, Wang YE (1983) Pharmacologic actions of lappaconitine hydrobromide. Yao Xue Xue Bao 18:579–584

    CAS  PubMed  Google Scholar 

  • 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 193:93–99

    Article  PubMed  Google Scholar 

  • 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 265:263–272

    CAS  PubMed  Google Scholar 

  • 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) 57:801–807

    Article  CAS  Google Scholar 

  • Wang YZ, Xiao YQ, Zhang C, Sun XM (2009b) Study of analgesic and anti-inflammatory effects of lappaconitine gelata. J Tradit Chin Med 29:141–145

    Article  PubMed  Google Scholar 

  • 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 7:43137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 499:499–505

    Article  CAS  PubMed  Google Scholar 

  • Wright SN (2001) Irreversible block of human heart (hH1) sodium channels by the plant alkaloid lappaconitine. Mol Pharmacol 59:183–192

    Article  CAS  PubMed  Google Scholar 

  • Wu HY, Mao XF, Fan H, Wang YX (2017) p38beta mitogen-activated protein kinase signaling mediates exenatide-stimulated microglial beta-endorphin expression. Mol Pharmacol 91:451–463

    Article  CAS  PubMed  Google Scholar 

  • Yuan CL, Wang XL (2012) Isolation of active substances and bioactivity of Aconitum sinomontanum Nakai. Nat Prod Res 26:2099–2102

    CAS  PubMed  Google Scholar 

  • 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 154:2452–2462

    Article  CAS  PubMed  Google Scholar 

  • 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 121:835–851

    Article  CAS  PubMed  Google Scholar 

  • 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:e936

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

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

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Author notes

  1. Ming-Li Sun and Jun-Ping Ao contributed equally to this work.

Authors and Affiliations

  1. King’s Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai, 200240, China

    Ming-Li Sun, Yi-Rui Wang, Qian Huang, Teng-Fei Li, Xin-Yan Li & Yong-Xiang Wang

  2. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China

    Jun-Ping Ao & Yong-Xiang Wang

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  1. Ming-Li Sun
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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.

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Correspondence to Yong-Xiang Wang.

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Sun, ML., Ao, JP., Wang, YR. et al. Lappaconitine, a C18-diterpenoid alkaloid, exhibits antihypersensitivity in chronic pain through stimulation of spinal dynorphin A expression. Psychopharmacology 235, 2559–2571 (2018). https://doi.org/10.1007/s00213-018-4948-y

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