Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw

Abstract

Cannabidiol, the major non-psychoactive component of marijuana, has various pharmacological actions of clinical interest. It is reportedly effective as an anti-inflammatory and anti-arthritic in murine collagen-induced arthritis. The present study examined the anti-inflammatory and anti-hyperalgesic effects of cannabidiol, administered orally (5–40 mg/kg) once a day for 3 days after the onset of acute inflammation induced by intraplantar injection of 0.1 ml carrageenan (1% w/v in saline) in the rat. At the end of the treatment prostaglandin E2 (PGE2) was assayed in the plasma, and cyclooxygenase (COX) activity, production of nitric oxide (NO; nitrite/nitrate content), and of other oxygen-derived free radicals (malondialdehyde) in inflamed paw tissues. All these markers were significantly increased following carrageenan.

Thermal hyperalgesia, induced by carrageenan and assessed by the plantar test, lasted 7 h. Cannabidiol had a time- and dose-dependent anti-hyperalgesic effect after a single injection. Edema following carrageenan peaked at 3 h and lasted 72 h; a single dose of cannabidiol reduced edema in a dose-dependent fashion and subsequent daily doses caused further time- and dose-related reductions.

There were decreases in PGE2 plasma levels, tissue COX activity, production of oxygen-derived free radicals, and NO after three doses of cannabidiol. The effect on NO seemed to depend on a lower expression of the endothelial isoform of NO synthase. In conclusion, oral cannabidiol has a beneficial action on two symptoms of established inflammation: edema and hyperalgesia.

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References

  1. Agha A, Gad MZ (1995) Lipid peroxidation and lysosomal integrity in different inflammatory models in rats: the effects of indomethacin and naftazone. Pharmacol Res 32:279–285

    CAS  PubMed  Google Scholar 

  2. Beckman JS, Beckman TW, Chen TW, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implication of endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:1620–1624

    CAS  PubMed  Google Scholar 

  3. Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, Moriello AS, Davis JB, Mechoulam R, Di Marzo V (2001) Molecular target for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 134:845–852

    CAS  PubMed  Google Scholar 

  4. Claxson A, Morris C, Blake D, Siren M, Halliwell B, Gustafsson T, Lofkvist B, Bergelin I (1990) The anti-inflammatory effects of D-myoinositol-1,2,6-triphosphate (PP56) on animal models of inflammation. Agents Actions 29:68–70

    PubMed  Google Scholar 

  5. Coffey RG, Yamamoto Y, Snella E, Pross S (1996) Tetrahydrocannabinol inhibition of macrophage nitric oxide production. Biochem Pharmacol 52:743–751

    Article  CAS  PubMed  Google Scholar 

  6. Conti S, Costa B, Colleoni M, Parolaro D, Giagnoni G (2002) Antiinflammatory action of endocannabinoid palmitoylethanolamide and the synthetic cannabinoid nabilone in a model of acute inflammation in the rat. Br J Pharmacol 135:181–187

    CAS  PubMed  Google Scholar 

  7. Costa B, Conti S, Giagnoni G, Colleoni M (2002) Therapeutic effect of the endogenous fatty acid amide, palmitoylethanolamide, in rat acute inflammation: inhibition of nitric oxide and cyclo-oxygenase systems. Br J Pharmacol 137:413–420

    Article  CAS  PubMed  Google Scholar 

  8. Di Rosa M, Willoughby DA (1971) Screens for anti-inflammatory drugs. J Pharm Pharmacol 23:297–300

    PubMed  Google Scholar 

  9. Evans FJ (1991) Cannabinoids: the separation of central from peripheral effects on a structural basis. Planta Med 57 [Suppl]:60–67

    Google Scholar 

  10. Formukong EA, Evans AT, Evans FJ (1988) Analgesic and anti-inflammatory activity of constituents of Cannabis sativa L. Inflammation 12:361–371

    CAS  PubMed  Google Scholar 

  11. Gierse JK, Koboldt CM, Walker MC, Siebert K, Isakson PC (1999) Kinetic basis for selective inhibition of cyclo-oxygenase. Biochem J 339:607–614

    Article  CAS  PubMed  Google Scholar 

  12. Griffiths HR, Dowling EJ, Sahinoglu T, Blake DR, Parnham M, Lunec J (1992) The selective protection afforded by ebselen against lipid peroxidation in a ROS-dependent model of inflammation. Agents Actions 36:107–111

    CAS  PubMed  Google Scholar 

  13. Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95:8268–8273

    CAS  PubMed  Google Scholar 

  14. Handy RL, Moore PK (1998) A comparison of the effects of L-NAME, 7-NI and L-NIL on carrageenan-induced hindpaw oedema and NOS activity. Br J Pharmacol 123:1083–1088

    Google Scholar 

  15. Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32:77–98

    CAS  PubMed  Google Scholar 

  16. Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, Feldmann M (2000) The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci USA 97:9561–9566

    CAS  PubMed  Google Scholar 

  17. Mechoulam R (1986) The pharmacohistory of Cannabis sativa. In: Mechoulam R (ed) Cannabinoids as therapeutic agents. CRC, Boca Raton, pp 1–19

  18. Misko TP, Schilling RJ, Salvemini D, Moore WM, Currie MG (1993) A fluorimetric assay for the measurement of nitrite in biological samples. Anal Biochem 214:11–16

    Article  CAS  PubMed  Google Scholar 

  19. Nakamura M, Ferreira SH (1987) A peripheral sympathetic component in inflammatory hyperalgesia. Eur J Pharmacol 135:145–153

    Article  CAS  PubMed  Google Scholar 

  20. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    CAS  PubMed  Google Scholar 

  21. Radi R, Beckman JS, Bush KM, Freeman BA (1991) Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. Arch Biochem Biophys 288:481–487

    CAS  PubMed  Google Scholar 

  22. Razdan RK (1986) Structure activity relationships in cannabinoids. Pharmacol Rev 38:75–149

    CAS  PubMed  Google Scholar 

  23. Rubbo H, Radi R, Trujillo M, Telleri R, Kalyanaraman B, Barnes S, Kirk M, Freeman BA (1994) Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. J Biol Chem 269:26066–26075

    CAS  PubMed  Google Scholar 

  24. Salvemini D, Wang ZQ, Bourdon DM, Stern MK, Currie MG, Manning PT (1996a) Evidence of peroxynitrite involvement in the carrageenan-induced rat paw edema. Eur J Pharmacol 303:217–220

    Article  CAS  PubMed  Google Scholar 

  25. Salvemini D, Wang ZQ, Wyatt PS, Bourdon DM, Marino MH, Manning PT, Currie MG (1996b) Nitric oxide: a key mediator in the early and late phase of carrageenan-induced rat paw inflammation. Br J Pharmacol 118:829–838

    CAS  PubMed  Google Scholar 

  26. Sanders J, Jackson DM, Starmer GA (1979) Interactions among the cannabinoids in the antagonism of the abdominal constriction response in the mouse. Psychopharmacology 61:281–285

    CAS  PubMed  Google Scholar 

  27. Showalter VM, Compton DR, Martin BR, Abood ME (1996) Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands. J Pharmacol Exp Ther 264:463–468

    Google Scholar 

  28. Sofia RD, Knobloch LC, Vassar HB (1973) The anti-edema activity of various naturally occurring cannabinoids. Res Commun Chem Pathol Pharmacol 6:909–918

    CAS  PubMed  Google Scholar 

  29. Sofia RD, Vassar HB, Knobloch LC (1975) Comparative analgesic activity of various naturally occurring cannabinoids in mice and rats. Psychopharmacologia 40:285–295

    CAS  PubMed  Google Scholar 

  30. Srivastava MD, Srivastava BI, Brouhard B (1998) Delta-9-tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmacology 40:179–185

    Article  CAS  PubMed  Google Scholar 

  31. Symons AM, Dowling EJ, Parke DV (1988) Lipid peroxidation, free radicals and experimental inflammation. Basic Life Sci 49:987–990

    CAS  PubMed  Google Scholar 

  32. Tracey WR, Nakane M, Kuk J, Budzig G, Klinghofer V, Harris R, Cartel G (1995) The nitric oxide synthase inhibitor, L-NG-monomethylarginine, reduces carrageenan-induced pleurisy in the rat. J Pharmacol Exp Ther 273:1295–1299

    CAS  PubMed  Google Scholar 

  33. Watzl B, Scuderi P, Watson RR (1991) Marijuana components stimulate human peripheral blood mononuclear cell secretion of interferon gamma and suppress interleukin-1 alpha in vitro. Int J Immunopharmacol 13:1091–1097

    CAS  PubMed  Google Scholar 

  34. Yoshikawa T, Kondo M (1981) In: Goto Y, Yagi K (eds) Lipid peroxide and disease. Igaku-shoin, Tokyo, p 210

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Acknowledgements

This work was supported by grants from the Italian Ministry for Education, University and Research (M.I.U.R.). The authors thank GW Pharma for kindly supplying cannabidiol.

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Correspondence to Barbara Costa.

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Costa, B., Colleoni, M., Conti, S. et al. Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn-Schmiedeberg's Arch Pharmacol 369, 294–299 (2004). https://doi.org/10.1007/s00210-004-0871-3

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Keywords

  • Cannabinoids
  • Cannabidiol
  • Carrageenan
  • Inflammation
  • Hyperalgesia
  • COX system
  • NO system