The leaves of Bougainvillea spectabilis suppressed inflammation and nociception in vivo through the modulation of glutamatergic, cGMP, and ATP-sensitive K+ channel pathways

Abstract Ethnopharmacological relevance Bougainvillea spectabilis is an ornamental shrub from Nyctaginaceae family, widely used in the traditional medicine in the treatment of pain, inflammation, and ulcer. Some research investigated the analgesic potential of this plant, however, the in-depth analysis of its antinociceptive properties and molecular mechanism(s) are yet to be revealed. Purpose of the study This study, therefore, investigated the antinociceptive potential of methanol extract of the leaves of B. spectabilis (MEBS) with possible molecular mechanism(s) of action using several pre-clinical models of acute and chronic pain in mice. Materials and methods The dry leaf powder of B. spectabilis was macerated with 100 % methanol, and then dried crude extract was used for in vivo experiments. Following the acute toxicity test with 500, 1000, and 2000 mg/kg b.w. doses of MEBS, the central antinociceptive activities of the extract (50, 100, and 200 mg/kg b.w.) were evaluated using hot plate and tail immersion tests, whereas the peripheral activities were investigated using acetic acid-induced writhing, formalin-induced licking and oedema, and glutamate-induced licking tests. Moreover, the possible involvements of cGMP and ATP-sensitive K+ channel pathways in the observed antinociceptive activities were also investigated using methylene blue (20 mg/kg) and glibenclamide (10 mg/kg), respectively. We also performed GC/MS-MS analysis of MEBS to identify the phyto-constituents and in silico modelling of the major compounds to identify potential targets. Results Our results demonstrated that MEBS (50, 100, and 200 mg/kg; b.w.) was not effective in suppression of centrally mediated pain in hot plate and tail immersion models. However, the extract was potent (at 100 and 200 mg/kg; b.w. doses) in reducing peripheral nociception in the acetic acid-induced writhing and inflammatory phase of formalin-induced nociceptive models. Further analyses revealed that MEBS could interfere with glutamatergic system, cGMP and ATP-sensitive K+ channel pathways to show its antinociceptive properties. GC/MS-MS analysis revealed 35 different phytochemicals with potent anti-inflammatory and antinociceptive properties including phytol, neophytadiene, 2,4-Di-tert-butylphenol, fucoxanthin, and Vit-E. Prediction analysis showed high intestinal absorption and low toxicity profile of these compounds. These phytochemicals were also found to interact with glutamatergic system, inhibit JAK/STAT pathway, scavenge nitric oxide and oxygen radicals, and inhibit expression of COX3, tumour necrosis factor, and histamine. Conclusion Taken together, these results suggest the antinociceptive potentials of MEBS which are mediated through glutamatergic, cGMP, and ATP-sensitive K+ channel pathways. These also suggest that MEBS could be beneficial in the treatment of complications associated with nociceptive pain.