Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis

Abstract

Osteoarthritis (OA) is a multifactorial joint disease, which includes joint degeneration, intermittent inflammation, and peripheral neuropathy. Cannabidiol (CBD) is a noneuphoria producing constituent of cannabis that has the potential to relieve pain. The aim of this study was to determine whether CBD is anti-nociceptive in OA, and whether inhibition of inflammation by CBD could prevent the development of OA pain and joint neuropathy. Osteoarthritis was induced in male Wistar rats (150-175 g) by intra-articular injection of sodium monoiodoacetate (MIA; 3 mg). On day 14 (end-stage OA), joint afferent mechanosensitivity was assessed using in vivo electrophysiology, whereas pain behaviour was measured by von Frey hair algesiometry and dynamic incapacitance. To investigate acute joint inflammation, blood flow and leukocyte trafficking were measured on day 1 after MIA. Joint nerve myelination was calculated by G-ratio analysis. The therapeutic and prophylactic effects of peripheral CBD (100-300 μg) were assessed. In end-stage OA, CBD dose-dependently decreased joint afferent firing rate, and increased withdrawal threshold and weight bearing (P < 0.0001; n = 8). Acute, transient joint inflammation was reduced by local CBD treatment (P < 0.0001; n = 6). Prophylactic administration of CBD prevented the development of MIA-induced joint pain at later time points (P < 0.0001; n = 8), and was also found to be neuroprotective (P < 0.05; n = 6-8). The data presented here indicate that local administration of CBD blocked OA pain. Prophylactic CBD treatment prevented the later development of pain and nerve damage in these OA joints. These findings suggest that CBD may be a safe, useful therapeutic for treating OA joint neuropathic pain.

Conflict of interest statement

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Figures

Figure 1.

Dose-dependent effect of CBD on joint afferent firing in established OA. Example of a single-unit recording whereby CBD attenuated firing evoked by noxious rotation (A). Cannabidiol (100, 200, or 300 μg i.a.) decreased afferent firing relative to baseline (B). (*P < 0.05 2-way ANOVA with Bonferroni post hoc test; n = 8). The dose-dependent effect of CBD treatment on afferent firing rate was averaged over the 15 minutes after administration (C). (****P < 0.0001, **P < 0.01 1-way ANOVA with Bonferroni post hoc test; n = 8). Data are mean values ± SEM. ANOVA, analysis of variance; CBD, cannabidiol; i.a., intra-arterial; OA, osteoarthritis.

Figure 2.

Dose-dependent effect of CBD on pain-related measures in established OA. Intra-articular injection of MIA produced secondary allodynia and weight-bearing deficits in the ipsilateral hind paw and hind limb, respectively, 14 days after MIA injection (****P < 0.0001, 1-way ANOVA with Dunnett post hoc test; n = 24). Cannabidiol (100, 200, or 300 μg i.artic. at BL]) improved hind paw withdrawal threshold (A) and hind limb weight bearing dose-dependently, over 4 hours. (****P < 0.0001, **P < 0.01, *P < 0.05 2-way ANOVA with Bonferroni post hoc test; n = 8). Data are mean values ± SEM. ANOVA, analysis of variance; BL, baseline, CBD, cannabidiol; MIA, sodium monoiodoacetate, OA, osteoarthritis; VEH, vehicle.

Figure 3.

Effect of contralaterally administered CBD on ipsilateral pain behaviour. The improvement in hind paw withdrawal threshold seen with ipsilateral CBD was not observed when CBD (300 μg i.artic.) was administered to the contralateral knee (A). Contralateral CBD did not significantly decrease hind paw weight bearing (B) when compared with ipsilateral CBD. (*P < 0.05, **P < 0.01 1-way ANOVA with Fisher post hoc test; n = 8-9). Data are mean values ± SEM. ANOVA, analysis of variance; CBD, cannabidiol; VEH, vehicle.

Figure 4.

Contribution of cannabinoid and noncannabinoid receptors to the analgesic effects of CBD. Both hind paw withdrawal threshold (A) and hind limb weight bearing (B) were unaltered compared with control after local administration of the CB1 receptor antagonist AM281 (75 μg) or CB2 receptor antagonist AM630 (75 μg). Hind paw withdrawal threshold (A) was reduced compared with control after local administration of the TRPV1 antagonist SB-366791 (30 μg), but hind limb weight bearing (B) was unaffected. (*P < 0.05, **P < 0.01 1-way ANOVA with Fisher post hoc test; n = 6-8). Data are mean values ± SEM. ANOVA, analysis of variance; CBD, cannabidiol; VEH, vehicle.

Figure 5.

Anti-inflammatory action of CBD on day 1 MIA-induced inflammation. When compared with naïve controls, intra-articular MIA significantly increased rolling (A) and adherent (B) leukocytes, and caused synovial hyperaemia (C) (****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05, P > 0.05, unpaired t test; n = 6-12). Over a 3-hour time course, CBD (300 μg) significantly decreased leukocyte rolling (A) leukocyte adherence (B) and knee joint blood flow (C) when compared to vehicle. (****P < 0.0001, **P < 0.01, *P < 0.05 2-way ANOVA with Bonferroni post hoc test; n = 6). Data are mean values ± SEM. ANOVA, analysis of variance; CBD, cannabidiol; MIA, sodium monoiodoacetate; PU, perfusion unit; VEH, vehicle.

Figure 6.

Contribution of cannabinoid and noncannabinoid receptors to the anti-inflammatory effects of CBD. The anti-rolling effect of CBD at 30 minutes was blocked (A) by CB2 receptor antagonist AM630 (75 μg) and TRPV1 antagonist SB-366791 (30 μg), but not CB1 receptor antagonist AM281 (75 μg). The anti-adherence effect of CBD in day 1 MIA joints was blocked by SB-366791 (B). (****P < 0.0001, ***P < 0.001 1-way ANOVA with Fisher LSD post hoc test; n = 60). Data are mean values ± SEM. ANOVA, analysis of variance; CBD, cannabidiol; MIA, sodium monoiodoacetate; VEH, vehicle.

Figure 7.

Effect of prophylactic CBD administration on the development of pain over 14 days post-MIA injection. Treating MIA knee joints with CBD (300 μg; s.c.; days 0–3) significantly improved von Frey hair withdrawal threshold over the 14-day development of OA when compared with vehicle (A). Pretreatment of MIA knee joints with CBD had no significant effect on hind limb weight bearing (B) (****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05 2-way ANOVA with Bonferroni post hoc test; n = 8). Data are mean values ± SEM. ANOVA, analysis of variance; CBD, cannabidiol; MIA, sodium monoiodoacetate; OA, osteoarthritis; s.c., subcutaneous; VEH, vehicle.

Figure 8.

Prophylactic CBD reduces joint nerve demyelination in MIA-induced OA. Representative sections of electron micrographs of axons found in saphenous nerves taken at day 14 from MIA treated with vehicle (A) (days 0–3), or CBD (300 μg; days 0–3). (B) G-ratio calculations showing that MIA-induced axonal demyelination is prevented by CBD treatment. Scale bar is 6 μm. (*P < 0.05 unpaired t test; n = 6 = 8). Data are presented as mean values ± SEM. CBD, cannabidiol; MIA, sodium monoiodoacetate; OA, osteoarthritis; VEH, vehicle.