Zerumbone, a monocyclic sesquiterpene from the wild ginger plant Zingiber zerumbet (L.) Smith, attenuates allodynia and hyperalgesia. Currently, its mechanisms of action in neuropathic pain conditions remain unclear. This study examines the involvement of potassium channels and opioid receptors in zerumbone-induced analgesia in a chronic constriction injury (CCI) neuropathic pain mice model. Male Institute of Cancer Research (ICR) mice were subjected to CCI and behavioral responses were tested on day 14. Responses toward mechanical allodynia and thermal hyperalgesia were tested with von Frey's filament and Hargreaves' tests, respectively. Symptoms of neuropathic pain were significantly alleviated following treatment with zerumbone (10 mg/kg; intraperitoneal, i.p.). However, when the voltage-dependent K+ channel blocker tetraethylammonium (TEA, 4 mg/kg; i.p.), ATP-sensitive K+ channel blocker, glibenclamide (GLIB, 10 mg/kg; i.p.); small-conductance Ca2+-activated K+ channel inhibitor apamin (APA, 0.04 mg/kg; i.p.), or large-conductance Ca2+-activated K+ channel inhibitor charybdotoxin (CHAR, 0.02 mg/kg; i.p.) was administered prior to zerumbone (10 mg/kg; i.p.), the antiallodynic and antihyperalgesic effects of zerumbone were significantly reversed. Additionally, non-specific opioid receptors antagonist, naloxone (NAL, 10 mg/kg; i.p.), selective µ-, δ- and κ-opioid receptor antagonists; β-funaltrexamine (β-FN, 40 mg/kg; i.p.), naltrindole (20 mg/kg; s.c.), nor-binaltorphamine (10 mg/kg; s.c.) respectively attenuated the antiallodynic and antihyperalgesic effects of zerumbone. This outcome clearly demonstrates the participation of potassium channels and opioid receptors in the antineuropathic properties of zerumbone. As various clinically used neuropathic pain drugs also share this similar mechanism, this compound is, therefore, a highly potential substitute to these therapeutic options.
Mitragyna speciosa is a tropical plant with narcotic effects. The antinociceptive effects of its crude extracts, bioactive compounds and structurally modified derivatives have been examined in rodent models. This review aims to summarize the evidence on the antinociceptive effects of M. speciosa and its derivatives and explore whether they can offer an alternative to morphine in pain management. Methanolic and alkaloid extracts of M. speciosa were shown to attenuate the nociceptive response in rodents. Mitragynine and 7-hydroxymitragynine offered better antinociceptive effects than crude extracts. Structurally modified derivatives of 7-hydroxymitragynine, such as MGM-9, MGM- 15, MGM-16, demonstrated superior antinociceptive effects compared to morphine. M. speciosa and its derivatives mainly act on the opioid receptor, but receptor subtypes specificity differs between each compound. The tolerance and adverse side effects of M. speciosa and its derivatives are similar with morphine. The affinity of MGM-9 on kappa-opioid receptor could potentially limit the effects of drug dependence. In conclusion, M speciosa derivatives can offer alternatives to morphine in controlling chronic pain. Structural modification of mitragynine and 7-hydroxymitragynine can generate compounds with higher potency and lesser side-effects. Human clinical trials are required to validate the use of these compounds in clinical setting.