Serotonin release mediates analgesia via opioidergic system and withdrawal symptoms in chronic kratom extract-treated mice

Kratom alleviates pain by activating μu-opioid receptors (MOR), which trigger serotonin release to produce analgesia. Serotonin also interferes drug abuse effect. This study aimed to determine the role of serotonin in kratom-induced pain relief and withdrawal symptoms in mice. The analgesic effect was assessed using the hot-plate test. To induce withdrawal symptoms, mice received naloxone after being treated with kratom extracts for five days at increasing doses. Another group of morphine-dependent mice was treated with kratom extracts to ameliorate their withdrawal symptoms. A molecular docking study and molecular dynamics were conducted to predict the binding target of alkaloid kratom for increasing serotonin levels. Chronic administration of kratom alkaloid extract (20 mg/kg) produced analgesic effects comparable to morphine (10 mg/kg). In contrast, kratom crude extracts (10 mg/kg and 20 mg/kg) demonstrated lower analgesia activity. This analgesic effect was mediated by MOR activation, leading to decreased intracellular cAMP and increased serotonin transmission. Repeated and increasing doses of crude or alkaloid kratom extracts (8 mg/kg to 45 mg/kg) produced less severe withdrawal symptoms than morphine. Increased dopamine and serotonin levels contributed to the onset of withdrawal symptoms. In the morphine group, treatment with kratom extracts increased serotonin levels while reducing dopamine. Molecular docking and molecular dynamics result revealed that kratom alkaloids interacts more readily with tryptophan hydroxylase, the enzyme responsible for serotonin biosynthesis. Kratom extracts have the potential to provide analgesic effects and withdrawal symptoms, both of which are mediated by elevated serotonin release. • The alkaloid extract of kratom produces an analgesic effect similar to morphine but with a longer duration of action. • MOR activation, decreased cAMP, and increased serotonin levels contribute to the analgesic effect, while dopamine levels remain unaffected. • Compare to morphine, alkaloid and crude extracts of kratom cause less severe withdrawal symptoms. • MOR activation, increased cAMP, elevated serotonin and dopamine levels contribute to the emergence of withdrawal symptoms. • In morphine-dependent mice, treatment with alkaloid and crude extracts of kratom increased serotonin levels but decreased dopamine levels.