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.
Cannabinoids Cannabidiol Carrageenan Inflammation Hyperalgesia COX system NO system
This is a preview of subscription content, log in to check access.
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.
Agha A, Gad MZ (1995) Lipid peroxidation and lysosomal integrity in different inflammatory models in rats: the effects of indomethacin and naftazone. Pharmacol Res 32:279–285PubMedGoogle Scholar
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 87:1620–1624PubMedGoogle Scholar
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 134:845–852PubMedGoogle Scholar
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 29:68–70PubMedGoogle Scholar
Coffey RG, Yamamoto Y, Snella E, Pross S (1996) Tetrahydrocannabinol inhibition of macrophage nitric oxide production. Biochem Pharmacol 52:743–751CrossRefPubMedGoogle Scholar
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 135:181–187PubMedGoogle Scholar
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 137:413–420CrossRefPubMedGoogle Scholar
Di Rosa M, Willoughby DA (1971) Screens for anti-inflammatory drugs. J Pharm Pharmacol 23:297–300PubMedGoogle Scholar
Evans FJ (1991) Cannabinoids: the separation of central from peripheral effects on a structural basis. Planta Med 57 [Suppl]:60–67Google Scholar
Formukong EA, Evans AT, Evans FJ (1988) Analgesic and anti-inflammatory activity of constituents of Cannabis sativa L. Inflammation 12:361–371PubMedGoogle Scholar
Gierse JK, Koboldt CM, Walker MC, Siebert K, Isakson PC (1999) Kinetic basis for selective inhibition of cyclo-oxygenase. Biochem J 339:607–614CrossRefPubMedGoogle Scholar
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 36:107–111PubMedGoogle Scholar
Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95:8268–8273PubMedGoogle Scholar
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 123:1083–1088Google Scholar
Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32:77–98PubMedGoogle Scholar
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 97:9561–9566PubMedGoogle Scholar
Mechoulam R (1986) The pharmacohistory of Cannabis sativa. In: Mechoulam R (ed) Cannabinoids as therapeutic agents. CRC, Boca Raton, pp 1–19Google Scholar
Misko TP, Schilling RJ, Salvemini D, Moore WM, Currie MG (1993) A fluorimetric assay for the measurement of nitrite in biological samples. Anal Biochem 214:11–16CrossRefPubMedGoogle Scholar
Nakamura M, Ferreira SH (1987) A peripheral sympathetic component in inflammatory hyperalgesia. Eur J Pharmacol 135:145–153CrossRefPubMedGoogle Scholar
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358PubMedGoogle Scholar
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 288:481–487PubMedGoogle Scholar
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 269:26066–26075PubMedGoogle Scholar
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 303:217–220CrossRefPubMedGoogle Scholar
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 118:829–838PubMedGoogle Scholar
Sanders J, Jackson DM, Starmer GA (1979) Interactions among the cannabinoids in the antagonism of the abdominal constriction response in the mouse. Psychopharmacology 61:281–285PubMedGoogle Scholar
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 264:463–468Google Scholar
Sofia RD, Knobloch LC, Vassar HB (1973) The anti-edema activity of various naturally occurring cannabinoids. Res Commun Chem Pathol Pharmacol 6:909–918PubMedGoogle Scholar
Sofia RD, Vassar HB, Knobloch LC (1975) Comparative analgesic activity of various naturally occurring cannabinoids in mice and rats. Psychopharmacologia 40:285–295PubMedGoogle Scholar
Srivastava MD, Srivastava BI, Brouhard B (1998) Delta-9-tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmacology 40:179–185CrossRefPubMedGoogle Scholar
Symons AM, Dowling EJ, Parke DV (1988) Lipid peroxidation, free radicals and experimental inflammation. Basic Life Sci 49:987–990PubMedGoogle Scholar
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 273:1295–1299PubMedGoogle Scholar
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 13:1091–1097PubMedGoogle Scholar
Yoshikawa T, Kondo M (1981) In: Goto Y, Yagi K (eds) Lipid peroxide and disease. Igaku-shoin, Tokyo, p 210Google Scholar