Advertisement

Psychopharmacology

, Volume 235, Issue 11, pp 3259–3271 | Cite as

Effect of cannabidiolic acid and ∆9-tetrahydrocannabinol on carrageenan-induced hyperalgesia and edema in a rodent model of inflammatory pain

  • Erin M. Rock
  • Cheryl L. Limebeer
  • Linda A. ParkerEmail author
Original Investigation

Abstract

Rationale

Cannabidiol (CBD), a non-intoxicating component of cannabis, or the psychoactive Δ9-tetrahydrocannabiol (THC), shows anti-hyperalgesia and anti-inflammatory properties.

Objectives

The present study evaluates the anti-inflammatory and anti-hyperalgesia effects of CBD’s potent acidic precursor, cannabidiolic acid (CBDA), in a rodent model of carrageenan-induced acute inflammation in the rat hind paw, when administered systemically (intraperitoneal, i.p.) or orally before and/or after carrageenan. In addition, we assess the effects of oral administration of THC or CBDA, their mechanism of action, and the efficacy of combined ineffective doses of THC and CBDA in this model. Finally, we compare the efficacy of CBD and CBDA.

Results

CBDA given i.p. 60 min prior to carrageenan (but not 60 min after carrageenan) produced dose-dependent anti-hyperalgesia and anti-inflammatory effects. In addition, THC or CBDA given by oral gavage 60 min prior to carrageenan produced anti-hyperalgesia effects, and THC reduced inflammation. The anti-hyperalgesia effects of THC were blocked by SR141716 (a cannabinoid 1 receptor antagonist), while CBDA’s effects were blocked by AMG9810 (a transient receptor potential cation channel subfamily V member 1 antagonist). In comparison to CBDA, an equivalent low dose of CBD did not reduce hyperalgesia, suggesting that CBDA is more potent than CBD for this indication. Interestingly, when ineffective doses of CBDA or THC alone were combined, this combination produced an anti-hyperalgesia effect and reduced inflammation.

Conclusion

CBDA or THC alone, as well as very low doses of combined CBDA and THC, has anti-inflammatory and anti-hyperalgesia effects in this animal model of acute inflammation.

Keywords

Inflammation Hyperalgesia Δ9-Tetrahydrocannabiol Cannabidiolic acid Cannabidiol Rat Carrageenan SR141716 AMG9810 

Notes

Acknowledgements

This work was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) Collaborative Research and Development Grant (CRDPJ 476416-14) to LAP in partnership with Prairie Plant Systems Inc., as well as a grant to LAP from NSERC (92056) and from Canadian Institute of Health Research (137122).

Compliance with ethical standards

All animal procedures complied with the Canadian Council on Animal Care and were approved by the Institutional Animal Care Committee (accredited by the Canadian Council on Animal Care).

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Ashkinazi IY, Vershinina EA (1999) Pain sensitivity in chronic psychoemotional stress in humans. Neurosci Behav Physiol 29:333–337CrossRefGoogle Scholar
  2. Baron EP, Lucas P, Eades J, Hogue O (2018) Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort. J Headache Pain 19:37.  https://doi.org/10.1186/s10194-018-0862-2 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Blake DR, Robson P, Ho M, Jubb RW, McCabe CS (2006) Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford) 45:50–52.  https://doi.org/10.1093/rheumatology/kei183 CrossRefGoogle Scholar
  4. Boggs DL, Nguyen JD, Morgenson D, Taffe MA, Ranganathan M (2017) Clinical and preclinical evidence for functional interactions of cannabidiol and Δ9-tetrahydrocannabinol. Neuropsychopharmacology 43:142–154.  https://doi.org/10.1038/npp.2017.209 CrossRefPubMedGoogle Scholar
  5. Bolognini D, Rock EM, Cluny NL, Cascio MG, Limebeer CL, Duncan M, Stott CG, Javid FA, Parker LA, Pertwee RG (2013) Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol 168:1456–1470.  https://doi.org/10.1111/bph.12043 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bornheim LM, Correia MA (1990) Selective inactivation of mouse liver cytochrome P-450IIIA by cannabidiol. Mol Pharmacol 38:319–326PubMedGoogle Scholar
  7. Bornheim LM, Correia MA (1991) Purification and characterization of the major hepatic cannabinoid hydroxylase in the mouse: a possible member of the cytochrome P-450IIC subfamily. Mol Pharmacol 40:228–234PubMedGoogle Scholar
  8. Carcieri C, Tomasello C, Simiele M, De N, Avataneo V, Canzoneri L et al (2018) Cannabinoids concentration variability in cannabis olive oil galenic preparations. J Pharm Pharmacol 70:143–149.  https://doi.org/10.1111/jphp.12845 CrossRefPubMedGoogle Scholar
  9. Casey SL, Atwal N, Vaughan CW (2017) Cannabis constituent synergy in a mouse neuropathic pain model. Pain 158:2452–2460.  https://doi.org/10.1097/j.pain.0000000000001051 CrossRefPubMedGoogle Scholar
  10. 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(1):181–187.  https://doi.org/10.1038/sj.bjp.0704466 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Cooper ZD, Comer SD, Haney M (2013) Comparison of the analgesic effects of dronabinol and smoked marijuana in daily marijuana smokers. Neuropsychopharmacology 38:1984–1992.  https://doi.org/10.1038/npp.2013.97 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Costa B, Colleoni M, Conti S, Parolaro D, Franke C, Trovato AE, Giagnoni G (2004a) 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.  https://doi.org/10.1007/s00210-004-0871-3 CrossRefGoogle Scholar
  13. Costa B, Giagnoni G, Franke C, Trovato AE, Colleoni M (2004b) Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. Br J Pharmacol 143:247–250.  https://doi.org/10.1038/sj.bjp.0705920 CrossRefPubMedGoogle Scholar
  14. Craft RM, Kandasamy R, Davis SM (2013) Sex differences in anti-allodynic, anti-hyperalgesic and anti-edema effects of Δ(9)-tetrahydrocannabinol in the rat. Pain 154:1709–1717.  https://doi.org/10.1016/j.pain.2013.05.017 CrossRefPubMedGoogle Scholar
  15. De Petrocellis L, Vellani V, Schiano-Moriello A, Marini P, Magherini PC, Orlando P et al (2008) Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther 325:1007–1015.  https://doi.org/10.1124/jpet.107.134809 CrossRefPubMedGoogle Scholar
  16. Ferrè L, Nuara A, Pavan G, Radaelli M, Moiola L, Rodegher M, Colombo B, Keller Sarmiento IJ, Martinelli V, Leocani L, Martinelli Boneschi F, Comi G, Esposito F (2016) Efficacy and safety of nabiximols (Sativex(®)) on multiple sclerosis spasticity in a real-life Italian monocentric study. Neurol Sci 37:235–242.  https://doi.org/10.1007/s10072-015-2392-x CrossRefPubMedGoogle Scholar
  17. Gavva NR, Tamir R, Qu Y, Klionsky L, Zhang TJ, Immke D, Wang J, Zhu D, Vanderah TW, Porreca F, Doherty EM, Norman MH, Wild KD, Bannon AW, Louis JC, Treanor JJ (2005) AMG 9810 [(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic properties. J Pharmacol Exp Ther 313:474–484.  https://doi.org/10.1124/jpet.104.079855 CrossRefPubMedGoogle Scholar
  18. Hammell DC, Zhang LP, Ma F, Abshire SM, McIlwrath SL, Stinchcomb AL et al (2016) Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. Eur J Pain 20:936–948.  https://doi.org/10.1002/ejp.818 CrossRefPubMedGoogle Scholar
  19. Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32:77–88CrossRefGoogle Scholar
  20. Hložek T, Uttl L, Kadeřábek L, Balíková M, Lhotková E, Horsley RR, Nováková P, Šíchová K, Štefková K, Tylš F, Kuchař M, Páleníček T (2017) Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC. Eur Neuropsychopharmacol 27:1223–1237.  https://doi.org/10.1016/j.euroneuro.2017.10.037 CrossRefPubMedGoogle Scholar
  21. Ibrahim EA, Gul W, Gul SW, Stamper BJ, Hadad GM, Abdel Salam RA, Ibrahim A, Ahmed S, Chandra S, Lata H, Radwan M, ElSohly M (2018) Determination of acid and neutral cannabinoids in extracts of different strains of Cannabis sativa using GC-FID. Planta Med 84:250–259.  https://doi.org/10.1055/s-0043-124088 CrossRefPubMedGoogle Scholar
  22. Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT (2013) An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manag 46:207–218.  https://doi.org/10.1016/j.jpainsymman.2012.07.014 CrossRefGoogle Scholar
  23. Katsidoni V, Kastellakis A, Panagis G (2013) Biphasic effects of Delta9- tetrahydrocannabinol on brain stimulation reward and motor activity. Int J Neuropsychopharmacol 16:2273–2284.  https://doi.org/10.1017/S1461145713000709 CrossRefPubMedGoogle Scholar
  24. Keselman HJ, Algina J, Kowalchuk RK (2001) The analysis of repeated measures designs: a review. Br J Math Stat Psychol 54:1–20CrossRefGoogle Scholar
  25. King KM, Myers AM, Soroka-Monzo AJ, Tuma RF, Tallarida RJ, Walker EA, Ward SJ (2017) Single and combined effects of Δ9 -tetrahydrocannabinol and cannabidiol in a mouse model of chemotherapy-induced neuropathic pain. Br J Pharmacol 174:2832–2841.  https://doi.org/10.1111/bph.13887 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Klein C, Karanges E, Spiro A, Wong A, Spencer J, Huynh T, Gunasekaran N, Karl T, Long LE, Huang XF, Liu K, Arnold JC, McGregor IS (2011) Cannabidiol potentiates Δ9-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats. Psychopharmacology 218:443–457.  https://doi.org/10.1007/s00213-011-2342-0 CrossRefPubMedGoogle Scholar
  27. Korczeniewska OA, Khan J, Tao Y, Eliav E, Benoliel R (2017) Effects of sex and stress on trigeminal neuropathic pain-like behavior in rats. J Oral Facial Pain Headache 31:381–397.  https://doi.org/10.11607/ofph.1807 CrossRefPubMedGoogle Scholar
  28. Langford RM, Mares J, Novotna A, Vachova M, Novakova I, Notcutt W, Ratcliffe S (2013) A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. J Neurol 260:984–997.  https://doi.org/10.1007/s00415-012-6739-4 CrossRefPubMedGoogle Scholar
  29. Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L et al (2006) Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 318:1375–1387.  https://doi.org/10.1124/jpet.106.105247 CrossRefPubMedGoogle Scholar
  30. Lodzki M, Godin B, Rakou L, Mechoulam R, Gallily R, Touitou E (2003) Cannabidiol-transdermal delivery and anti-inflammatory effect in a murine model. J Control Release 93:377–387CrossRefGoogle Scholar
  31. Lötsch J, Weyer-Menkhoff I, Tegeder I (2018) Current evidence of cannabinoid-based analgesia obtained in preclinical and human experimental settings. Eur J Pain 22:471–484.  https://doi.org/10.1002/ejp.1148 CrossRefPubMedGoogle Scholar
  32. Nackley AG, Makriyannis A, Hohmann AG (2003) Selective activation of cannabinoid CB(2) receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation. Neuroscience 119:747–757.  https://doi.org/10.1016/S0306-4522(03)00126-X CrossRefPubMedGoogle Scholar
  33. Novelli GP, Peduto VA, Bertol E, Mari F, Pieraccioli E (1983) Analgesic interaction between nitrous oxide and delta-9-tetrahydrocannabinol in the rat. Br J Anaesth 55:997–1000CrossRefGoogle Scholar
  34. Ogborne AC, Smart RG, Adlaf EM (2000) Self-reported medical use of marijuana: a survey of the general population. CMAJ 162:1685–1686PubMedPubMedCentralGoogle Scholar
  35. Pellesi L, Licata M, Verri P, Vandelli D, Palazzoli F, Marchesi F (2018) Pharmacokinetics and tolerability of oral cannabis preparations in patients with medication overuse headache (MOH)—a pilot study. Eur J Clin Pharmacol.  https://doi.org/10.1007/s00228-018-2516-3 CrossRefGoogle Scholar
  36. Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT (2012) Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain 13:438–449.  https://doi.org/10.1016/j.jpain.2012.01.003 CrossRefPubMedGoogle Scholar
  37. Prescott WR, Gold LH, Martin BR (1992) Evidence for separate neuronal mechanisms for the discriminative stimulus and catalepsy induced by delta 9-THC in the rat. Psychopharmacology 107:117–124CrossRefGoogle Scholar
  38. Reid MJ, Bornheim LM (2001) Cannabinoid-induced alterations in brain disposition of drugs of abuse. Biochem Pharmacol 61:1357–1367CrossRefGoogle Scholar
  39. Reiman A, Welty M, Solomon P (2017) Cannabis as a substitute for opioid-based pain medication: patient self-report. Cannabis Cannabinoid Res 2:160–166.  https://doi.org/10.1089/can.2017.0012 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Rock EM, Parker LA (2013) Effect of low doses of cannabidiolic acid and ondansetron on LiCl-induced conditioned gaping (a model of nausea-induced behaviour) in rats. Br J Pharmacol 169:685–692.  https://doi.org/10.1111/bph.12162 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Rock EM, Limebeer CL, Navaratnam R, Sticht MA, Bonner N, Engeland K, Downey R, Morris H, Jackson M, Parker LA (2014) A comparison of cannabidiolic acid with other treatments for anticipatory nausea using a rat model of contextually elicited conditioned gaping. Psychopharmacology 231:3207–3215.  https://doi.org/10.1007/s00213-014-3498-1 CrossRefPubMedGoogle Scholar
  42. Rock EM, Limebeer CL, Parker LA (2015) Effect of combined doses of Δ9-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea using rat (Sprague-Dawley) models of conditioned gaping. Psychopharmacology 232:4445–4454.  https://doi.org/10.1007/s00213-015-4080-1 CrossRefPubMedGoogle Scholar
  43. Rock EM, Connolly C, Limebeer CL, Parker LA (2016) Effect of combined oral doses of ∆9-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea in rat models. Psychopharmacology 233:3353–3360.  https://doi.org/10.1007/s00213-016-4378-7 CrossRefPubMedGoogle Scholar
  44. Rog DJ, Nurmikko TJ, Friede T, Young CA (2005) Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 65:812–819.  https://doi.org/10.1212/01.wnl.0000176753.45410.8b CrossRefGoogle Scholar
  45. Rog DJ, Nurmikko TJ, Young CA (2007) Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clin Ther 29:2068–2079.  https://doi.org/10.1016/j.clinthera.2007.09.013 CrossRefPubMedGoogle Scholar
  46. Romero-Sandoval A, Nutile-McMenemy N, DeLeo JA (2008) Spinal microglial and perivascular cell cannabinoid receptor type 2 activation reduces behavioral hypersensitivity without tolerance after peripheral nerve injury. Anesthesiology 108:722–734.  https://doi.org/10.1097/ALN.0b013e318167af74 CrossRefPubMedPubMedCentralGoogle Scholar
  47. Russo M, Naro A, Leo A, Sessa E, D'Aleo G, Bramanti P et al (2016) Evaluating Sativex® in neuropathic pain management: a clinical and neurophysiological assessment in multiple sclerosis. Pain Med 17:1145–1154.  https://doi.org/10.1093/pm/pnv080 CrossRefPubMedGoogle Scholar
  48. Sofia RD, Knobloch LC, Vassar HB (1973a) The anti-edema activity of various naturally occurring cannabinoids. Res Commun Chem Pathol Pharmacol 6:909–918PubMedGoogle Scholar
  49. Sofia RD, Nalepa SD, Harakal JJ, Vassar HB (1973b) Anti-edema and analgesic properties of delta9-tetrahydrocannabinol (THC). J Pharmacol Exp Ther 186:646–655PubMedGoogle Scholar
  50. Taffe MA, Creehan KM, Vandewater SA (2015) Cannabidiol fails to reverse hypothermia or locomotor suppression induced by Delta(9) -tetrahydrocannabinol in Sprague–Dawley rats. Br J Pharmacol 172:1783–1791.  https://doi.org/10.1111/bph.13024 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Tékus V, Bölcskei K, Kis-Varga A, Dézsi L, Szentirmay E, Visegrády A, Horváth C, Szolcsányi J, Pethő G (2010) Effect of transient receptor potential vanilloid 1 (TRPV1) receptor antagonist compounds SB705498, BCTC and AMG9810 in rat models of thermal hyperalgesia measured with an increasing-temperature water bath. Eur J Pharmacol 641:135–141.  https://doi.org/10.1016/j.ejphar.2010.05.052 CrossRefPubMedGoogle Scholar
  52. Uesugi K, Sekiguchi M, Kikuchi S, Konno S (2011) The effect of repeated restraint stress in pain-related behavior induced by nucleus pulposus applied on the nerve root in rats. Eur Spine J 20:1885–1891.  https://doi.org/10.1007/s00586-011-1877-4 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Ujváry I, Hanuš L (2016) Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy. Cannabis Cannabinoid Res 1:90–101.  https://doi.org/10.1089/can.2015.0012 CrossRefPubMedPubMedCentralGoogle Scholar
  54. Varvel SA, Wiley JL, Yang R, Bridgen DT, Long K, Lichtman AH, Martin BR (2006) Interactions between THC and cannabidiol in mouse models of cannabinoid activity. Psychopharmacology 186:226–234.  https://doi.org/10.1007/s00213-006-0356-9 CrossRefPubMedGoogle Scholar
  55. Vermersch P, Trojano M (2016) Tetrahydrocannabinol:cannabidiol oromucosal spray for multiple sclerosis-related resistant spasticity in daily practice. Eur Neurol 76:216–226.  https://doi.org/10.1159/000449413 CrossRefPubMedGoogle Scholar
  56. Wang YH, Avula B, ElSohly MA, Radwan MM, Wang M, Wanas AS, Mehmedic Z, Khan I (2018) Quantitative determination of Δ9-THC, CBG, CBD, their acid precursors and five other neutral cannabinoids by UHPLC-UV-MS. Planta Med 84:260–266.  https://doi.org/10.1055/s-0043-124873 CrossRefPubMedGoogle Scholar
  57. Ward SJ, Ramirez MD, Neelakantan H, Walker EA (2011) Cannabidiol prevents the development of cold and mechanical allodynia in paclitaxel-treated female C57Bl6 mice. Anesth Analg 113:947–950.  https://doi.org/10.1213/ANE.0b013e3182283486 CrossRefPubMedPubMedCentralGoogle Scholar
  58. Ward SJ, McAllister SD, Kawamura R, Murase R, Neelakantan H, Walker EA (2014) Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT(1A) receptors without diminishing nervous system function or chemotherapy efficacy. Br J Pharmacol 171:636–645.  https://doi.org/10.1111/bph.12439 CrossRefPubMedPubMedCentralGoogle Scholar
  59. Ware MA, Wang T, Shapiro S, Collet JP, COMPASS study team (2015) Cannabis for the management of pain: assessment of safety study (COMPASS). J Pain 16:1233–1242.  https://doi.org/10.1016/j.jpain.2015.07.014 CrossRefGoogle Scholar
  60. Winter CA, Risley EA, Nuss GW (1962) Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc Soc Exp Biol Med 111:544–547CrossRefGoogle Scholar
  61. Woodhams SG, Chapman V, Finn DP, Hohmann AG, Neugebauer V (2017) The cannabinoid system and pain. Neuropharmacology 124:105–120.  https://doi.org/10.1016/j.neuropharm.2017.06.015 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Department of Psychology and Collaborative Neuroscience ProgramUniversity of GuelphGuelphCanada

Personalised recommendations