Plasma glucose-lowering effect of tramadol in streptozotocin-induced diabetic rats.
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 mu-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 mu-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 mu-receptors by tramadol can increase the utilization of glucose and/or decrease hepatic gluconeogenesis to lower plasma glucose in diabetic rats lacking insulin.
Cheng
J T
JT
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan. jtcheng@mail.ncku.edu.tw
Liu
I M
IM
Chi
T C
TC
Tzeng
T F
TF
Lu
F H
FH
Chang
C J
CJ
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4; D006003:Glycogen / Q000096:biosynthesis; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000032:analysis / Q000235:genetics; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D009270:Naloxone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000737:chemistry / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000502:physiology; D014147:Tramadol / Q000008:administration & dosage / Q000494:pharmacology*
D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D009292:Narcotic Antagonists; D009294:Narcotics; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; C495694:Slc2a4 protein, rat; D009270:Naloxone; D014147:Tramadol; C034643:naloxonazine; D006003:Glycogen; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose