Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis

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.

Conflict of interest statement

Conflicts of interest

None declared.

© 2015 European Pain Federation - EFIC®

Figures

Figure 1

Assessment of knee joint inflammation. (A) Ipsilateral knee joint circumference was significantly increased in rats with adjuvant-induced monoarthritis and significantly decreased after four consecutive days of transdermal cannabidiol (CBD) treatment using 6.2 or 62.3 mg/day doses (*p < 0.01; one-way ANOVA). (B) Pain scores (median) were maximal 3 days after adjuvant-induced monoarthritis and were significantly reduced by 6.2 and 62.3 mg/day CBD (*p < 0.05; Kruskal–Wallis test). (C–E) H&E staining of the synovial membrane from (C) a naïve rat, (D) after adjuvant-induced monoarthritis and (E) after adjuvant-induced monoarthritis treated with 6.2 mg/day transdermal CBD. (F) Bar graph shows high doses of CBD (combined 6.2 and 62.3 mg/day doses) reduced synovial membrane thickening more than 50%. (n = 4–7 rats per group) (*p < 0.001; one-way ANOVA).

Figure 2

Transdermal cannabidiol (CBD) reduced monoarthritis-induced hind paw heat hypersensitivity. (A) Transdermal CBD significantly increased heat paw withdrawal latency in rats with monoarthritis, (B) but had no effect in naïve rats (*p < 0.01 vs. day 3, one-way ANOVA). (C, D) In the open-field test, transdermal CBD exerts no detectable effect on times spent in spontaneous exploratory activity or resting. (n = 5 per group and CBD dose)

Figure 3

Immunocytochemical localization of inflammatory biomarkers. (A) CGRP and (B) OX42 are shown in ipsilateral spinal cord dorsal horn for naïve, complete Freud’s adjuvant (CFA) arthritic and cannabidiol (CBD) treated CFA arthritic rats. (C) TNFα is shown in the ipsilateral dorsal root ganglia of naïve, CFA arthritic and CBD treated CFA arthritic rats. Bar = 100 μm.

Figure 4

Quantification of pro-inflammatory biomarkers in the lumbar spinal cord and dorsal root ganglia (DRG). Increases in spinal cord (A) CGRP and (B) OX42 and (C) DRG TNFα after adjuvant-induced monoarthritis are reduced to baseline levels by high doses of transdermal cannabidiol. (n = 4–6 animals per group) (*p < 0.05; one-way ANOVA).