The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain

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Abstract

Cannabidiol, the major psycho-inactive component of cannabis, has substantial anti-inflammatory and immunomodulatory effects. This study investigated its therapeutic potential on neuropathic (sciatic nerve chronic constriction) and inflammatory pain (complete Freund's adjuvant intraplantar injection) in rats. In both models, daily oral treatment with cannabidiol (2.5–20 mg/kg to neuropathic and 20 mg/kg to adjuvant-injected rats) from day 7 to day 14 after the injury, or intraplantar injection, reduced hyperalgesia to thermal and mechanical stimuli. In the neuropathic animals, the anti-hyperalgesic effect of cannabidiol (20 mg/kg) was prevented by the vanilloid antagonist capsazepine (10 mg/kg, i.p.), but not by cannabinoid receptor antagonists. Cannabidiol's activity was associated with a reduction in the content of several mediators, such as prostaglandin E2 (PGE2), lipid peroxide and nitric oxide (NO), and in the over-activity of glutathione-related enzymes. Cannabidiol only reduced the over-expression of constitutive endothelial NO synthase (NOS), without significantly affecting the inducible form (iNOS) in inflamed paw tissues. Cannabidiol had no effect on neuronal and iNOS isoforms in injured sciatic nerve. The compound's efficacy on neuropathic pain was not accompanied by any reduction in nuclear factor-κB (NF-κB) activation and tumor necrosis factor α (TNFα) content. The results indicate a potential for therapeutic use of cannabidiol in chronic painful states.

Introduction

The pharmacological profile of cannabidiol, the major psycho-inactive component of cannabis, which is a physiologically important isomer of delta9-tetrahydrocannabinol, the main psychoactive constituent of the plant, has received excellent reviews recently (Pertwee, 2004, Russo and Guy, 2006). Cannabidiol has anti-anxiety, anti-psychotic, neuroprotective and anticonvulsant effects, influencing the metabolism of delta9-tetrahydrocannabinol by blocking its conversion to the more psychoactive 11-hydroxy tetrahydrocannabinol for direct interaction with cytochrome P450 enzymes; it is a powerful anti-oxidant and has noteworthy anti-inflammatory and immunomodulatory effects (Malfait et al., 2000). We recently showed its therapeutic efficacy in a rat model of acute inflammation induced by intraplantar (i.pl.) injection of carrageenan, where cannabidiol had a time- and dose-dependent anti-hyperalgesic effect when given orally 2 h after the induction of inflammation (Costa et al., 2004a).

Cannabidiol has recently been shown to act as a transient receptor potential vanilloid 1 (TRPV1) agonist with potency equivalent to capsaicin, while also inhibiting the reuptake and hydrolysis of anandamide (Bisogno et al., 2001). Last year, Health Canada approved Sativex (Cannabis sativa L. extract; the ratio of delta9-tetrahydrocannabinol to cannabidiol is 2.7 mg: 2.5 mg per spray); this new drug, developed by GW Pharmaceutical, proved successful as adjunctive treatment for the symptomatic relief of neuropathic pain in adults with multiple sclerosis (Rog et al., 2005) and rheumatoid arthritis (Blake et al., 2006).

The pathogenesis in nociceptive and inflammatory reactions is complex and multifunctional and is triggered and maintained by various intracellular mediators. One of these, tumor necrosis factor α (TNFα), is particularly important in triggering a cascade of other cytokines and induces the up-regulation of cyclooxygenase 2 protein while also increasing prostaglandin E2 (PGE2) levels, probably through the transcription nuclear factor-κB (NF-κB), inducing the activation of genes encoding for both cyclooxygenase and inducible nitric-oxide synthase (iNOS) (Schafers et al., 2004). Stimulation of TNFα causes a respiratory burst in phagocytes, characterized by a sharp increase in oxygen uptake; so reactive oxygen intermediates are formed (Murray and Cohn, 1980). Nitric oxide (NO) is an endogenous modulator whose diverse biological functions include acting as a neurotransmitter in the brain and other parts of the body; it may have pro-inflammatory effects including vasodilatation and edema (Clancy and Abramson, 1995). High levels of TNFα, reactive oxygen intermediates and NO can cause inflammation, damage cells and tissues, and contribute to hypersensitivity to pain.

The main aim of this work was therefore to evaluate the therapeutic efficacy of prolonged treatment with cannabidiol on pain in models of neuropathy and chronic inflammation. We also examined whether cannabidiol inhibited the production of nociceptive and inflammatory mediators involved in development and maintenance of these chronic painful states.

Section snippets

Animals

Male Wistar rats (200–220 g, Harlan, Milan, Italy) were housed five per cage at constant temperature (22 ± 2 °C), with a 12:12 h light/dark cycle, and free access to food and water at all times for at least a week before being used. The experiments were carried out in accordance with current guidelines for the care of laboratory animals (Permit no. 94/2000A) and ethical guidelines for investigations of experimental pain in conscious animals (Zimmermann, 1983). For all studies animals were

Anti-hyperalgesic effect of cannabidiol in neuropathic and inflamed rats

The scores for withdrawal latency for both thermal and mechanical stimuli were tested 7 and 14 days after surgery (Fig. 1A and B) or i.pl. injection (Fig. 1C and D). Before surgery or injection, rats withdrew their left and right hind paws from radiant heat with a latency of about 10 s and sustained a mechanical force of about 100 g. Seven days after sciatic nerve ligature or adjuvant injection, there was a significant decrease (about 50%) in both thermal and mechanical withdrawal latency in

Discussion

The main finding reported here is that the non-psychoactive cannabis constituent cannabidiol reverses both thermal and mechanical hyperalgesia after seven days of repeated oral treatment, in two different models of persistent pain, the chronic constriction injury model of neuropathic pain and the complete Freund's adjuvant-induced model of inflammatory pain. This result is noteworthy, since the treatment started on day 7 when the pathology was well established, suggesting that cannabidiol's

Acknowledgments

This work was supported by grants from the Italian Ministry of Education, University and Research (MIUR). We are grateful to GW Pharmaceuticals and Sanofi-Aventis for kindly supplying cannabidiol and CB receptor antagonists, and thank J.D. Baggott for editing.

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