Transdermal Cannabidiol Reduces Inflammation and Pain-related Behaviours in a Rat Model of Arthritis

Overview

Journal Eur J Pain

Publisher Wiley

Specialties Critical Care
Neurology
Psychiatry

Date 2015 Oct 31

PMID 26517407

Citations 109

Authors

D C Hammell

L P Zhang

F Ma

S M Abshire

S L McIlwrath

A L Stinchcomb

K N Westlund

Affiliations

Soon will be listed here.

Abstract

Background: Current arthritis treatments often have side-effects attributable to active compounds as well as route of administration. Cannabidiol (CBD) attenuates inflammation and pain without side-effects, but CBD is hydrophobic and has poor oral bioavailability. Topical drug application avoids gastrointestinal administration, first pass metabolism, providing more constant plasma levels.

Methods: This study examined efficacy of transdermal CBD for reduction in inflammation and pain, assessing any adverse effects in a rat complete Freund's adjuvant-induced monoarthritic knee joint model. CBD gels (0.6, 3.1, 6.2 or 62.3 mg/day) were applied for 4 consecutive days after arthritis induction. Joint circumference and immune cell invasion in histological sections were measured to indicate level of inflammation. Paw withdrawal latency (PWL) in response to noxious heat stimulation determined nociceptive sensitization, and exploratory behaviour ascertained animal's activity level.

Results: Measurement of plasma CBD concentration provided by transdermal absorption revealed linearity with 0.6-6.2 mg/day doses. Transdermal CBD gel significantly reduced joint swelling, limb posture scores as a rating of spontaneous pain, immune cell infiltration and thickening of the synovial membrane in a dose-dependent manner. PWL recovered to near baseline level. Immunohistochemical analysis of spinal cord (CGRP, OX42) and dorsal root ganglia (TNFα) revealed dose-dependent reductions of pro-inflammatory biomarkers. Results showed 6.2 and 62 mg/day were effective doses. Exploratory behaviour was not altered by CBD indicating limited effect on higher brain function.

Conclusions: These data indicate that topical CBD application has therapeutic potential for relief of arthritis pain-related behaviours and inflammation without evident side-effects.

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References

Kochukov M, McNearney T, Yin H, Zhang L, Ma F, Ponomareva L . Tumor necrosis factor-alpha (TNF-alpha) enhances functional thermal and chemical responses of TRP cation channels in human synoviocytes. Mol Pain. 2009; 5:49. PMC: 3152771. DOI: 10.1186/1744-8069-5-49. View

Whyte L, Ryberg E, Sims N, Ridge S, Mackie K, Greasley P . The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc Natl Acad Sci U S A. 2009; 106(38):16511-6. PMC: 2737440. DOI: 10.1073/pnas.0902743106. View

McGaraughty S, Chu K, Perner R, Didomenico S, Kort M, Kym P . TRPA1 modulation of spontaneous and mechanically evoked firing of spinal neurons in uninjured, osteoarthritic, and inflamed rats. Mol Pain. 2010; 6:14. PMC: 2841076. DOI: 10.1186/1744-8069-6-14. View

Hastings R, Ding T, Butt S, Gadsby K, Zhang W, Moots R . Neutropenia in patients receiving anti-tumor necrosis factor therapy. Arthritis Care Res (Hoboken). 2010; 62(6):764-9. DOI: 10.1002/acr.20037. View

Nahin R, Byers M . Adjuvant-induced inflammation of rat paw is associated with altered calcitonin gene-related peptide immunoreactivity within cell bodies and peripheral endings of primary afferent neurons. J Comp Neurol. 1994; 349(3):475-85. DOI: 10.1002/cne.903490311. View

Coffey R, Yamamoto Y, Snella E, Pross S . Tetrahydrocannabinol inhibition of macrophage nitric oxide production. Biochem Pharmacol. 1996; 52(5):743-51. DOI: 10.1016/0006-2952(96)00356-5. View

Zimmer A, Zimmer A, Hohmann A, Herkenham M, Bonner T . Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci U S A. 1999; 96(10):5780-5. PMC: 21937. DOI: 10.1073/pnas.96.10.5780. View

Cunnane G, Bjork L, Ulfgren A, Lindblad S, FitzGerald O, Bresnihan B . Quantitative analysis of synovial membrane inflammation: a comparison between automated and conventional microscopic measurements. Ann Rheum Dis. 1999; 58(8):493-9. PMC: 1752933. DOI: 10.1136/ard.58.8.493. View

Berman J, Symonds C, Birch R . Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain. 2004; 112(3):299-306. DOI: 10.1016/j.pain.2004.09.013. View

10.

Begg M, Pacher P, Batkai S, Osei-Hyiaman D, Offertaler L, Mo F . Evidence for novel cannabinoid receptors. Pharmacol Ther. 2005; 106(2):133-45. DOI: 10.1016/j.pharmthera.2004.11.005. View

11.

Berckmans R, Nieuwland R, Kraan M, Schaap M, Pots D, Smeets T . Synovial microparticles from arthritic patients modulate chemokine and cytokine release by synoviocytes. Arthritis Res Ther. 2005; 7(3):R536-44. PMC: 1174949. DOI: 10.1186/ar1706. View

12.

Szabo A, Helyes Z, Sandor K, Bite A, Pinter E, Nemeth J . Role of transient receptor potential vanilloid 1 receptors in adjuvant-induced chronic arthritis: in vivo study using gene-deficient mice. J Pharmacol Exp Ther. 2005; 314(1):111-9. DOI: 10.1124/jpet.104.082487. View

13.

Keeble J, Russell F, Curtis B, Starr A, Pinter E, Brain S . Involvement of transient receptor potential vanilloid 1 in the vascular and hyperalgesic components of joint inflammation. Arthritis Rheum. 2005; 52(10):3248-56. DOI: 10.1002/art.21297. View

14.

Guo L, Schluesener H . Acute but not chronic stimulation of glial cells in rat spinal cord by systemic injection of lipopolysaccharide is associated with hyperalgesia. Acta Neuropathol. 2006; 112(6):703-13. DOI: 10.1007/s00401-006-0135-z. View

15.

Costa B, Trovato A, Comelli F, Giagnoni G, Colleoni M . The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur J Pharmacol. 2006; 556(1-3):75-83. DOI: 10.1016/j.ejphar.2006.11.006. View

16.

Shan S, Qi-Liang M, Hong C, Tingting L, Mei H, Haili P . Is functional state of spinal microglia involved in the anti-allodynic and anti-hyperalgesic effects of electroacupuncture in rat model of monoarthritis?. Neurobiol Dis. 2007; 26(3):558-68. PMC: 2681292. DOI: 10.1016/j.nbd.2007.02.007. View

17.

Brown A . Novel cannabinoid receptors. Br J Pharmacol. 2007; 152(5):567-75. PMC: 2190013. DOI: 10.1038/sj.bjp.0707481. View

18.

Ryberg E, Larsson N, Sjogren S, Hjorth S, Hermansson N, Leonova J . The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007; 152(7):1092-101. PMC: 2095107. DOI: 10.1038/sj.bjp.0707460. View

19.

Helmick C, Felson D, Lawrence R, Gabriel S, Hirsch R, Kwoh C . Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008; 58(1):15-25. DOI: 10.1002/art.23177. View

20.

Akopian A, Ruparel N, Patwardhan A, Hargreaves K . Cannabinoids desensitize capsaicin and mustard oil responses in sensory neurons via TRPA1 activation. J Neurosci. 2008; 28(5):1064-75. PMC: 6671418. DOI: 10.1523/JNEUROSCI.1565-06.2008. View