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Open Access 01-01-2017 | Original Paper

Ephedra Herb extract activates/desensitizes transient receptor potential vanilloid 1 and reduces capsaicin-induced pain

Authors: Shunsuke Nakamori, Jun Takahashi, Sumiko Hyuga, Toshiko Tanaka-Kagawa, Hideto Jinno, Masashi Hyuga, Takashi Hakamatsuka, Hiroshi Odaguchi, Yukihiro Goda, Toshihiko Hanawa, Yoshinori Kobayashi

Published in: Journal of Natural Medicines | Issue 1/2017

Abstract

Kampo medicines containing Ephedra Herb (EH) such as eppikajutsubuto and makyoyokukanto are used to treat myalgia, arthralgia, and rheumatism. The analgesic effects of these Kampo medicines are attributed to the anti-inflammatory action of EH. However, the molecular mechanism of the analgesic effect of EH remains to be clarified. In this study, the effects of EH extract (EHE) on transient receptor potential vanilloid 1 (TRPV1), a nonselective ligand-gated cation channel, which plays an essential role in nociception on sensory neurons, were investigated using mTRPV1/Flp-In293 cells (stable mouse TRPV1-expressing transfectants). Administration of EHE increased the intracellular Ca²⁺ concentration in these cells, which was inhibited by the TRPV1 antagonist, N-(4-tert-butylphenyl)-1,2-dihydro-4-(3-chloropyridine-2-yl) tetrahydropyrazine-1-carboxamide (BCTC), indicating that EHE activated TRPV1. Examination of EHE-induced nociceptive pain in vivo revealed that an intradermal (i.d.) injection of EHE into the hind paw of mice induced paw licking, a pain-related behavior, and that the extract increased paw licking times in a dose-dependent manner. The EHE-induced paw licking was also inhibited by BCTC. An i.d. injection of EHE 30 min before administration of capsaicin decreased capsaicin-induced paw licking times. Similarly, oral administration of the extract also suppressed capsaicin-induced paw licking, without affecting the physical performance of the mice. These results suggest that EHE suppresses capsaicin-induced paw licking by regulating TRPV1 activity. Thus, the antinociceptive effects of EHE seem to be produced by its direct action on sensory neurons through TRPV1.

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Ministry of Health, Labor and Welfare of Japan (2010) The Japanese pharmacopoeia, 16th edn. Tokyo

Urabe A, Shimada K, Kwai S (2015) Today’s drug therapy in 2015. Nankodo, Tokyo

Toriizuka K (2003) Monographs of pharmacological research on traditional herbal medicines (Shoyaku no yakuso yakuri). Ishiyaku, Tokyo

Batz F, Hitchens K, Jellin JM (2012) Pharmacist’s letter/Prescriber’s letter natural medicines comprehensive database, 13th edn. Therapeutic Research Faculty, Stockton

Yeom MJ, Lee HC, Kim GH, Lee HJ, Shim I, Oh SK, Kang SK, Hahm DH (2006) Anti-arthritic effects of Ephedra sinica STAPF herb-acupuncture: inhibition of lipopolysaccharide-induced inflammation and adjuvant-induced polyarthritis. J Pharmacol Sci 100:41–50CrossRefPubMed

Kasahara Y, Hikino H, Tsurufuji S, Watanabe M, Ohuchi K (1985) Antiinflammatory actions of ephedrines in acute inflammations. Planta Med 4:325–331CrossRef

Hyuga S, Hyuga M, Oshima M, Maruyama M, Kamakura H, Yamashita T, Yoshimura M, Amakura Y, Hakamatsuka T, Odaguchi H, Goda Y, Hanawa T (2016) Ephedrine alkaloids-free Ephedra Herb extract: a safer alternative to ephedra with comparable analgesic, anticancer, and anti-influenza activities. J Nat Med 70:571–583CrossRefPubMedPubMedCentral

Barrot M (2012) Tests and models of nociception and pain in rodents. Neuroscience 211:39–50CrossRefPubMed

Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824CrossRefPubMed

10.

Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21:531–543CrossRefPubMed

11.

Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sørgård M, Di Marzo V, Julius D, Högestätt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400:452–457CrossRefPubMed

12.

Hwang SW, Cho H, Kwak J, Lee SY, Kang CJ, Jung J, Cho S, Min KH, Suh YG, Kim D, Oh U (2000) Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci USA 97:6155–6160CrossRefPubMedPubMedCentral

13.

Szolcsányi J, Sándor Z (2012) Multisteric TRPV1 nocisensor: a target for analgesics. Trends Pharmacol Sci 33:646–655CrossRefPubMed

14.

Planells-Cases R, Garcìa-Sanz N, Morenilla-Palao C, Ferrer-Montiel A (2005) Functional aspects and mechanisms of TRPV1 involvement in neurogenic inflammation that leads to thermal hyperalgesia. Pflug Arch 451:151–159CrossRef

15.

Lewin GR, Nykjaer A (2014) Pro-neurotrophins, sortilin, and nociception. Eur J Neurosci 39:363–374CrossRefPubMedPubMedCentral

16.

O’Neill J, Brock C, Olesen AE, Andresen T, Nilsson M, Dickenson AH (2012) Unravelling the mystery of capsaicin: a tool to understand and treat pain. Pharmacol Rev 64:939–971CrossRefPubMedPubMedCentral

17.

Ohkawara S, Tanaka-Kagawa T, Furukawa Y, Nishimura T, Jinno H (2010) Activation of the human transient receptor potential vanilloid subtype 1 by essential oils. Biol Pharm Bull 33:1434–1437CrossRefPubMed

18.

Ohkawara S, Tanaka-Kagawa T, Furukawa Y, Jinno H (2012) Methylglyoxal activates the human transient receptor potential ankyrin 1 channel. J Toxicol Sci 37:831–835CrossRefPubMed

19.

Melo CM, Maia JL, Cavalcante IJ, Lima MA, Vieira GA, Silveira ER, Rao VS, Santos FA (2006) 12-Acetoxyhawtriwaic acid lactone, a diterpene from Egletes viscosa, attenuates capsaicin-induced ear edema and hindpaw nociception in mice: possible mechanisms. Planta Med 72:584–589CrossRefPubMed

20.

Rosland JH, Hunskaar S, Hole K (1990) Diazepam attenuates morphine antinociception test-dependently in mice. Pharmacol Toxicol 66:382–386CrossRefPubMed

21.

Wang S, Chuang HH (2011) C-terminal dimerization activates the nociceptive transduction channel transient receptor potential vanilloid 1. J Biol Chem 286:40601–40607CrossRefPubMedPubMedCentral

22.

Valenzano KJ, Grant ER, Wu G, Hachicha M, Schmid L, Tafesse L, Sun Q, Rotshteyn Y, Francis J, Limberis J, Malik S, Whittemore ER, Hodges D (2003) N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: I. in vitro characterization and pharmacokinetic properties. J Pharmacol Exp Ther 306:377–386CrossRefPubMed

23.

Pomonis JD, Harrison JE, Mark L, Bristol DR, Valenzano KJ, Walker K (2003) N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: II. in vivo characterization in rat models of inflammatory and neuropathic pain. J Pharmacol Exp Ther 306:387–393CrossRefPubMed

24.

Okumi H, Takashima K, Matsumoto K, Namiki T, Terasawa K, Horie S (2012) Dietary agonists of TRPV1 inhibit gastric acid secretion in mice. Planta Med 78:1801–1806CrossRefPubMed

25.

Gavva NR, Tamir R, Klionsky L, Norman MH, Louis JC, Wild KD, Treanor JJ (2005) Proton activation does not alter antagonist interaction with the capsaicin-binding pocket of TRPV1. Mol Pharmacol 68:1524–1533PubMed

26.

Meotti FC, Lemos de Andrade E, Calixto JB (2014) TRP modulation by natural compounds. Handb Exp Pharmacol 223:1177–1238CrossRefPubMed

27.

Kobayashi Y (2003) The nociceptive and anti-nociceptive effects of evodiamine from fruits of Evodia rutaecarpa in mice. Planta Med 69:425–428CrossRefPubMed

28.

Anand P, Bley K (2011) Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br J Anaesth 107:490–502CrossRefPubMedPubMedCentral

29.

Webster LR, Peppin JF, Murphy FT, Tobias JK, Vanhove GF (2012) Tolerability of NGX-4010, a capsacin 8% patch, in conjunction with three topical anesthetic formulations for the treatment of neuropathic pain. J Pain Res 5:7–13CrossRefPubMedPubMedCentral

30.

Mainka T, Malewicz NM, Baron R, Enax-Krumova EK, Treede RD, Maier C (2016) Presence of hyperalgesia predicts analgesic efficacy of topically applied capsaicin 8% in patients with peripheral neuropathic pain. Eur J Pain 20:116–129CrossRefPubMed

31.

Touska F, Marsakova L, Teisinger J, Vlachova V (2011) A “cute” desensitization of TRPV1. Curr Pharm Biotechnol 12:122–129CrossRefPubMed

32.

Koplas PA, Rosenberg RL, Oxford GS (1997) The role of calcium in the desensitization of capsaicin responses in rat dorsal root ganglion neurons. J Neurosci 17:3525–3537CrossRefPubMed

33.

Mandadi S, Numazaki M, Tominaga M, Bhat MB, Armati PJ, Roufogalis BD (2004) Activation of protein kinase C reverses capsaicin-induced calcium-dependent desensitization of TRPV1 ion channels. Cell Calcium 35:471–478CrossRefPubMed

34.

Mohapatra DP, Nau C (2005) Regulation of Ca²⁺-dependent desensitization in the vanilloid receptor TRPV1 by calcineurin and cAMP-dependent protein kinase. J Biol Chem 280:13424–13432CrossRefPubMed

35.

Numazaki M, Tominaga T, Takeuchi K, Murayama N, Toyooka H, Tominaga M (2003) Structural determinant of TRPV1 desensitization interacts with calmodulin. Proc Natl Acad Sci USA 100:8002–8006CrossRefPubMedPubMedCentral

36.

Rosenbaum T, Gordon-Shaag A, Munari M, Gordon SE (2004) Ca²⁺/calmodulin modulates TRPV1 activation by capsaicin. J Gen Physiol 123:53–62CrossRefPubMedPubMedCentral

37.

Lishko PV, Procko E, Jin X, Phelps CB, Gaudet R (2007) The ankyrin repeats of TRPV1 bind multiple ligands and modulate channel sensitivity. Neuron 54:905–918CrossRefPubMed

38.

Sanz-Salvador L, Andrés-Borderia A, Ferrer-Montiel A, Planells-Cases R (2012) Agonist- and Ca²⁺-dependent desensitization of TRPV1 channel targets the receptor to lysosomes for degradation. J Biol Chem 287:19462–19471CrossRefPubMedPubMedCentral

39.

Kennedy WR, Vanhove GF, Lu SP, Tobias J, Bley KR, Walk D, Wendelschafer-Crabb G, Simone DA, Selim MM (2010) A randomized, controlled, open-label study of the long-term effects of NGX-4010, a high-concentration capsaicin patch, on epidermal nerve fiber density and sensory function in healthy volunteers. J Pain 11:579–587CrossRefPubMed

40.

Wei P, Huo HL, Ma QH, Li HC, Xing XF, Tan XM, Luo JB (2014) Pharmacokinetic comparisons of five ephedrine alkaloids following oral administration of four different Mahuang-Guizhi herb-pair aqueous extracts ratios in rats. J Ethnopharmacol 155:642–648CrossRefPubMed

41.

Kaneko Y, Szallasi A (2014) Transient receptor potential (TRP) channels: a clinical perspective. Br J Pharmacol 171:2474–2507CrossRefPubMedPubMedCentral

42.

Gavva NR, Treanor JJ, Garami A, Fang L, Surapaneni S, Akrami A, Alvarez F, Bak A, Darling M, Gore A, Jang GR, Kesslak JP, Ni L, Norman MH, Palluconi G, Rose MJ, Salfi M, Tan E, Romanovsky AA, Banfield C, Davar G (2008) Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 136:202–210CrossRefPubMed

43.

Rowbotham MC, Nothaft W, Duan WR, Wang Y, Faltynek C, McGaraughty S, Chu KL, Svensson P (2011) Oral and cutaneous thermosensory profile of selective TRPV1 inhibition by ABT-102 in a randomized healthy volunteer trial. Pain 152:1192–1200CrossRefPubMed

Title: Ephedra Herb extract activates/desensitizes transient receptor potential vanilloid 1 and reduces capsaicin-induced pain
Authors: Shunsuke Nakamori
Jun Takahashi
Sumiko Hyuga
Toshiko Tanaka-Kagawa
Hideto Jinno
Masashi Hyuga
Takashi Hakamatsuka
Hiroshi Odaguchi
Yukihiro Goda
Toshihiko Hanawa
Yoshinori Kobayashi
Publication date: 01-01-2017
Publisher: Springer Japan
Published in: Journal of Natural Medicines / Issue 1/2017
Print ISSN: 1340-3443
Electronic ISSN: 1861-0293
DOI: https://doi.org/10.1007/s11418-016-1034-9

Keynote webinar | Spotlight on medication adherence

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Ephedra Herb extract activates/desensitizes transient receptor potential vanilloid 1 and reduces capsaicin-induced pain

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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