Caracterização pré-clínica das propriedades antinociceptivas da ayahuasca

Abstract

Neuropathic pain affects a significant portion of the global population. The clinical management of neuropathic pain is challenging due to the low efficacy of currently available treatments, which motivates the search for new therapeutic options. Several studies show that psychedelics promote analgesic effects in different chronic pain conditions. Ayahuasca (AYA) is a psychedelic brew used by many religious groups worldwide. The therapeutic potential of AYA is well-documented in the treatment of psychiatric conditions such as depression and drug addiction. However, despite the anecdotal evidence that AYA promotes analgesic effects in the religious context, this effect is still poorly studied. Therefore, this study aimed to investigate and characterize the antinociceptive effects of AYA. The antinociceptive effect of oral treatments with AYA was assessed in male Swiss or C57BL/6 mice in the formalin test, Complete Freund's Adjuvant (CFA) model of inflammation, tail flick test, and partial sciatic nerve ligation model of neuropathic pain. Motor coordination and spontaneous locomotion were assessed in the rota-rod and open field tests, respectively. Possible mechanisms of antinociception were investigated by assays of pharmacological antagonism and immunohistochemically assessing Fos expression in brain areas that modulate nociception. Parameters suggestive of systemic toxicity were investigated following acute or multiple exposures to AYA. Chemical characterization of AYA was made by HPLC and the antinociceptive effect of its major component, harmine, was tested in experimental neuropathy. AYA (24 - 3000 µL/kg) dose-dependently reduced formalin-induced pain-like behaviors and CFA-induced mechanical allodynia but did not affect CFA-induced paw edema or tail flick latency. During experimental painful neuropathy, single treatments with AYA (24 - 3000 µL/kg) reduced mechanical allodynia; daily treatments once or twice a day for 14 days promoted consistent and sustained antinociception. The antinociceptive effect of AYA (600 µL/kg) was reverted by bicuculline (GABAA receptor antagonist; 1 mg/kg) and methysergide (non-selective serotonergic antagonist; 5 mg/kg), but not by naloxone (non-selective opioid antagonist; 5 mg/kg), phaclofen (GABAB receptor antagonist; 2 mg/kg), and rimonabant (CB1 inverse agonist; 10 mg/kg), suggesting the role of GABAA and serotonergic receptors in AYAinduced antinociception. AYA increased Fos expression in the ventrolateral periaqueductal gray and nucleus raphe magnus 1 h after the treatment, but not after 6 h or 14 days of daily treatments. AYA (600 µL/kg) acutely or twice a day for 14 days did not alter mice’s motor function, spontaneous locomotion, body weight, food and water intake, hematological, biochemical, and histopathological parameters. Harmine (3.5 mg/kg, orally), the major component present in AYA, promoted consistent antinociception during experimental neuropathy. Taken together, the results of this study allow the conclusion that AYA promoted consistent antinociceptive effects in different mouse models of pain without inducing detectable toxic effects. Harmine is at least partially accountable for the antinociceptive properties of AYA.