Cannabidiol engages the peripheral endogenous opioid system to produce analgesia in neuropathic mice

Cannabidiol (CBD) has been getting attention from the scientific community regarding its potential for the treatment of different conditions, such as epilepsy, anxiety, and pain. This potential can be useful in clinical practice as an alternative or as an adjuvant alongside conventional therapeutic approaches; however, its mechanisms of action should be best described for its more effective application. Thus, our study aimed to evaluate whether the peripheral opioid system is involved in the analgesic mechanism of cannabidiol administered systemically for the treatment of neuropathic pain. Male Swiss mice were subjected to the sciatic constriction injury, and their nociceptive threshold was evaluated using the mechanical paw pressure test. Cannabidiol 20 mg/Kg produced an antinociceptive effect. Bestatin (400 µg/paw), a selective aminopeptidase-N inhibitor, potentiates the intermediate analgesic response of CBD at the dose of 2 mg/Kg. Naloxone (50 µg/paw), a non-selective opioid receptor antagonist, reversed the CBD-mediated analgesia. CTOP (5, 10, and 20 µg/paw) and naltrindole (30, 60, and 120 µg/paw), μ and Δ opioid receptor antagonists, but not norBNI (200 µg/paw), a κ opioid receptor antagonist, partially reversed the CBD analgesia. Thus, our study shows that cannabidiol may induce activation of opioid receptors in the periphery as a part of its analgesic mechanism in neuropathic pain.