Serotonin enhances β-endorphin secretion to lower plasma glucose in streptozotocin-induced diabetic rats

Although serotonin, serotonin uptake inhibitors and serotonin precursors (including tryptophan or 5-hydroxytryptophan) are known to have hypoglycemic action in rodents or human, it is not clear whether serotonin has hypoglycemic effect in streptozotocin-induced diabetic rats (STZ-diabetic rats). The aim of this study was to investigate the action of serotonin in regulating the plasma glucose STZ-diabetic rats. Plasma glucose, insulin, β-endorphin and adrenaline were assessed after intraperitoneal administration of serotonin. Serotonin produced hypoglycemic effects without altering plasma insulin and adrenaline levels but increasing β-endorphin level in STZ-diabetic rats. The glycogen content in soleus muscle was increased at 90 min after application of serotonin (0.3 mg/kg) in STZ-diabetic rats. Dihydroergotamine (non-selective 5-HT receptor blocker) and pimozide (5-HT7 receptor blocker) abolished the hypoglycemic effect of serotonin in STZ-diabetic rats. Serotonin-induced hypoglycemic effect in association with the increase of β-endorphin release was abolished in bilaterally adrenalectomized STZ-diabetic rats. In isolated adrenal gland of STZ-diabetic rats, the increase of β-endorphin secretion in response to serotonin was reduced by either dihydroergotamine or pimozide. Pretreatment with naloxone (1.0 mg/kg, i.p.) prevented serotonin-induced plasma glucose lowering effect in STZ-diabetic rats. The results demonstrated that serotonin may activate 5-HT7 receptor on rat adrenal gland to enhance of β-endorphin secretion, which then stimulates the opioid receptor to increase peripheral glucose utilization, resulting in decreased plasma glucose levels in STZ-diabetic rats.