Avaliação do efeito antinociceptivo do canabidiol na dor neuropática e mecanismos endógenos envolvidos neste evento

Abstract

Introduction: Cannabidiol (CBD) is the second most abundant pharmacologically active component present in the Cannabis sp. Unlike THC, the main psychoactive component responsible for the signs commonly observed in people who make recreational use of Cannabis, CBD has no psychotomimetic effects and has recently received significant interest from the scientific community due to its potential as a pharmacological agent in the treatment of anxiety and sleep disorders. In addition, it is known that cannabidiol has n excellent anti-inflammatory potential and can be used to treat some types of inflammatory pain. In this context, the potential of cannabidiol as an analgesic agent is known, but little is known about its efficiency in the treatment of neuropathic pain, a difficult-to-treat pain which greatly impacts the quality of life of patients suffering from this condition. In addition, the treatments available for neuropathic pain are limited and do not always bring complete relief from the painful sensation. For this reason, new pharmacological approaches are needed to improve treatment for these patients. Aim: The present study aims to evaluate the analgesic mechanism of cannabidiol administered systemically for the acute treatment of neuropathic pain and determine the endogenous mechanisms involved with this analgesia. Methods: Neuropathic pain was induced by sciatic nerve constriction surgery, and the nociceptive threshold was measured using the paw compression test in mice. Cannabidiol was administered intraperitoneally, and all other drugs were administered intraplantar, apart from drugs used in the motor coordination assessment test. Results: Sciatic nerve constriction surgery efficiently induced neuropathy, and CBD caused dose-dependent antinociception and had a maximum effect at the highest dose of 20 mg/kg. Such a dose is not capable of causing sedation or ataxia since the animals spent similar times on the RotaRod test as animals injected with saline. NAN-190 and SB366791, selective antagonists of 5-HT1A and TRPV1 receptors, respectively, reversed the antinociceptive effect induced by CBD. Similarly, AM251 and AM630, selective cannabinoid CB1 and CB2 receptor antagonists, respectively, also reversed antinociception caused by 20 mg/kg of CBD. Parallel to that, the inhibition of hydrolysis and reuptake of anandamide and 2-AG using MAFP, VDM11, and JZL184, respectively, potentiated the antinociception produced by an intermediate dose of 2 mg/kg of CBD. The selective µ and δ opioid receptor antagonists, CTOP and naltrindole, respectively, reversed the antinociception caused by CBD. However, Nor-BNI, a selective κ opioid receptor antagonist, did not cause alteration in CBD-induced antinociception. Hydrolysis inhibition of endogenous opioid peptides with bestatin also potentiates the antinociceptive effect of an intermediate dose of CBD. After assessing the intracellular pathway in the antinociceptive effect of CBD, the inhibition of PI3Kγ with AS605240 reversed the CBD-induced antinociception in a dose-dependent manner. The non-selective inhibition of nitric oxide synthase enzymes with L-NOarg, as well as the selective inhibition of nNOS enzymes using L-NPA, reversed the dose-dependent antinociception induced by CBD. However, the selective inhibition of iNOS and eNOS, using L-NIL and L-NIO, respectively, did not alter CBD-induced antinociception. Interestingly, the inhibition of cGMP production using ODQ, a selective soluble guanylate cyclase inhibitor, did not alter CBD-mediated antinociception, but selective blocking of ATP-sensitive K+ channels, using glibenclamide, dose-dependently reversed CBD-induced antinociception. Conclusion: Cannabidiol has an antinociceptive effect when administered systemically and this effect is mediated by the activation of cannabinoid and opioid receptors and via the PI3Kγ/NOS/NO/KATP pathway in peripheral tissues. Financial support: CNPq and CAPES.