Plasma Glucose–Lowering Effect of Tramadol in Streptozotocin-Induced Diabetic Rats

Plasma Glucose–Lowering Effect of Tramadol in Streptozotocin-Induced Diabetic Rats Juei-Tang Cheng 1 , I-Min Liu 1 , Tzong-Cherng Chi 1 , Thing-Fong Tzeng 3 , Feng-Hwa Lu 2 and Chih Jen Chang 2 1 Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan 2 Department of Family Medicine, College of Medicine, National Cheng Kung University, Tainan City, Taiwan 3 Department of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan Abstract The effect of tramadol on the plasma glucose level of streptozotocin (STZ)-induced diabetic rats was investigated. A dose-dependent lowering of plasma glucose was seen in the fasting STZ-induced diabetic rats 30 min after intravenous injection of tramadol. This effect of tramadol was abolished by pretreatment with naloxone or naloxonazine at doses sufficient to block opioid μ-receptors. However, response to tramadol was not changed in STZ-induced diabetic rats receiving p -chlorophenylalanine at a dose sufficient to deplete endogenous 5-hydroxytrptamine (5-HT). Therefore, mediation of 5-HT in this action of tramadol is ruled out. In isolated soleus muscle, tramadol enhanced the uptake of radioactive glucose in a concentration-dependent manner. The stimulatory effects of tramadol on glycogen synthesis were also seen in hepatocytes isolated from STZ-induced diabetic rats. The blockade of these actions by naloxone and naloxonazine indicated the mediation of opioid μ-receptors. The mRNA and protein levels of the subtype 4 form of glucose transporter in soleus muscle were increased after repeated treatments for 4 days with tramadol in STZ-induced diabetic rats. Moreover, similar repeated treatments with tramadol reversed the elevated mRNA and protein levels of phosphoenolpyruvate carboxykinase in the liver of STZ-induced diabetic rats. These results suggest that activation of opioid μ-receptors by tramadol can increase the utilization of glucose and/or decrease hepatic gluconeogenesis to lower plasma glucose in diabetic rats lacking insulin. Footnotes Address correspondence and reprint requests to Juei-Tang Cheng, Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan R.O.C. 70101. E-mail: jtcheng{at}mail.ncku.edu.tw . Received for publication 21 March 2001 and accepted in revised form 13 September 2001. 2-DG, 2-[1- 14 C]deoxy- d -glucose; 5-HIAA, 5-hydroxyindole acetic acid; 5-HT, 5-hydroxytrptamine; GLU