Antinociceptive Activity of the Hydro-Ethanolic Extract of the Leaves of Mallotus Oppositifolius (Geiseler) Mull. Arg. in Acute and Chronic Pain Models

Abstract

BACKGROUND: Mallotus oppositifolius is a medicinal plant commonly used in folk medicine to treat disorders involving pain and inflammation, among other ailments. However, the potential of this herb for the treatment of pain has only rudimentary scientific validation. The study sought to investigate the analgesic activity of the hydro-ethanolic extract of the leaves of M. oppositifolius (MOE) in order to provide detailed scientific justification for its traditional folkloric use. METHODS: Preliminary phytochemical screening was conducted on the MOE. Antinociceptive activity of MOE (30, 100 and 300 mg/kg) in acute pain models was evaluated using the formalin test, the acetic acid-induced writhing assay and the hot plate test. The mechanism of antinociception was evaluated by employing various antagonists in the formalin test including naloxone (2 mg/kg), glibenclamide (8 mg/kg), theophylline (10 mg/kg), ondansetron (0.5 mg/kg), yohimbine (3 mg/kg), nifedipine (10 mg/kg) and atropine (5 mg/kg). For the chronic pain model, peripheral neuropathy was induced in ICR mice using paclitaxel (2 mg/kg, i.p.) for 5 days and the effect of the extract on paclitaxel-induced peripheral neuropathy was evaluated daily for 5 days post induction using the Randall-Selitto test for mechanical hyperalgesia, hot plate test for thermal hyperalgesia and cold water at 4℃ for cold allodynia with pregabalin (10, 30 and 100 mg/kg) as the positive control. Sub-chronic toxicity study was carried out with male Sprague-Dawley rats divided into four groups; group 1 received vehicle p.o. while groups 2-4 were orally treated with MOE daily at 30, 100 and 300 mg/kg for 90 days consecutively. At the end of the test mice were sacrificed for their organs for histopathological analysis and their whole blood and serum for haematological and biochemical analysis respectively. RESULTS: Phytochemical screening confirmed the presence of secondary metabolites including saponins, alkaloids, flavonoids, glycosides, sterols, tannins and reducing sugars. MOE together with morphine and diclofenac (positive controls) showed significant (P<0.05) and dose-dependent decrease in the nociceptive scores in the formalin test, the acetic acid induced writhing assay and an increase in antinociceptive scores in the hot plate test. Naloxone, theophylline, ondansetron, glibenclamide, atropine, yohimbine and nifedipine failed to block the antinociceptive effects of MOE (100 mg/kg) in the formalin test. The extract significantly (P<0.05) and dose-dependently increased the paw withdrawal latencies to mechanical and thermal hyperalgesia after the 5–day induction of neuropathy with paclitaxel in mice. In the 90-day sub-chronic toxicity study, data analysis of mortality, body weight gain, clinical observations, haematology, biochemistry, organ weights and histopathological findings did not show significant differences between control and treated groups. CONCLUSION: The oral administration of a hydro-ethanolic leaf extract of Mallotus oppositifolius produces dose-dependent antinociceptive effects in formalin, acetic acid-induced and thermal acute pain tests, and also significantly inhibited mechanical and thermal hyperalgesia in paclitaxel-induced peripheral neuropathy in mice. There was no extracttreatment related toxicity in rats following a 90-day daily oral administration. The findings support the traditional uses of the plant in alleviating pain.