Effects of alkaloid-rich extract from Mitragyna speciosa (Korth.) Havil. on naloxone-precipitated morphine withdrawal symptoms and local field potential in the nucleus accumbens of mice

J Ethnopharmacol. 2017 Aug 17;208:129-137. doi: 10.1016/j.jep.2017.07.008. Epub 2017 Jul 5.


Ethnopharmacological relevance: Mitragyna speciosa (Korth.) Havil. (M. speciosa) is among the most well-known plants used in ethnic practice of Southeast Asia. It has gained increasing attention as a plant with potential to substitute morphine in addiction treatment program. However, its action on the central nervous system is controversial.

Aim of the study: This study investigated the effects of M. speciosa alkaloid extract on naloxone-precipitated morphine withdrawal and neural signaling in the nucleus accumbens (NAc, brain reward center) of mice.

Materials and methods: The effects of M. speciosa alkaloid extract and mitragynine, a pure major constituent, on naloxone-precipitated morphine withdrawal were examined. Male Swiss Albino (ICR) mice were rendered dependent on morphine before injection with naloxone, a nonspecific opioid antagonist, to induce morphine withdrawal symptoms. The intensity of naloxone-precipitated morphine withdrawal was assessed from jumping behavior and diarrhea induced during a period of morphine withdrawal. To test possible addictive effect of M. speciosa alkaloid extract, mice were implanted with intracranial electrode into the NAc for local field potential (LFP) recording. Following M. speciosa alkaloid extract (80mg/kg) and morphine (15mg/kg) treatment, LFP power spectra and spontaneous motor activity were analyzed in comparison to control levels.

Results: One-way ANOVA and multiple comparisons revealed that M. speciosa alkaloid extract (80 and 100mg/kg) significantly decreased the number of jumping behavior induced by morphine withdrawal whereas mitragynine did not. Additionally, M. speciosa alkaloid extract significantly decreased dry and wet fecal excretions induced by morphine withdrawal. LFP analysis revealed that morphine significantly decreased alpha (9.7-12Hz) and increased low gamma (30.3-44.9Hz) and high gamma (60.5-95.7Hz) powers in the NAc whereas M. speciosa alkaloid extract did not. Spontaneous motor activity was significantly increased by morphine but not M. speciosa alkaloid extract.

Conclusions: Taken together, M. speciosa alkaloid extract, but not mitragynine, attenuated the severity of naloxone-precipitated morphine withdrawal symptoms. Neural signaling in the NAc and spontaneous motor activity were sensitive to morphine but not M. speciosa alkaloid extract. Therefore, treatment with the M. speciosa alkaloid extract may be useful for opiate addiction treatment program.

Keywords: Mitragyna speciose; Morphine withdrawal; Naloxone; Nucleus accumbens; Opioid; Reward.

MeSH terms

  • Alkaloids / therapeutic use*
  • Analgesics, Opioid*
  • Animals
  • Behavior, Animal / drug effects
  • Diarrhea / drug therapy
  • Male
  • Mice, Inbred ICR
  • Mitragyna*
  • Morphine*
  • Naloxone
  • Narcotic Antagonists
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / physiology
  • Plant Extracts / therapeutic use*
  • Plant Leaves
  • Secologanin Tryptamine Alkaloids / therapeutic use
  • Substance Withdrawal Syndrome / drug therapy*
  • Substance Withdrawal Syndrome / etiology


  • Alkaloids
  • Analgesics, Opioid
  • Narcotic Antagonists
  • Plant Extracts
  • Secologanin Tryptamine Alkaloids
  • Naloxone
  • Morphine
  • mitragynine