Increase of opioid mu-receptor gene expression in streptozotocin-induced diabetic rats.
Opioids play an important role in the regulation of glucose homeostasis. In the previous report, we showed that activation of opioid mu-receptors produced a plasma glucose lowering effect in diabetic rats lacking insulin. In the present study, we found that the response of opioid mu-receptor is more sensitive in streptozotocin-induced diabetic rats (STZ-diabetic rats) than in normal rats. Intravenous injection of loperamide, an agonist of opioid mu-receptors, induced a dose-dependent decrease of plasma glucose from 3 microg/kg to 60 microg/kg in fasting STZ-diabetic rats. However, loperamide decreased the plasma glucose of normal fasting rats at the doses of 0.3 mg/kg to 1.5 mg/kg, which were much higher than those needed to produce the same effect in diabetic rats. The plasma glucose-lowering action of loperamide at the dose effective in normal rats disappeared in opioid mu-receptor knockout mice, while the plasma glucose-lowering response to loperamide was still observed in wild-type mice. This opens the possibility of mediation through opioid mu-receptor in the plasma glucose-lowering action of loperamide. Moreover, the mRNA level of opioid mu-receptor in the liver markedly increased in STZ-diabetic rats compared to normal rats. Normalization of plasma glucose concentrations in STZ-diabetic rats with exogenous insulin or phlorizin reversed mRNA and protein levels of opioid mu-receptor in the liver after 4 days of treatment. This shows that correction of hyperglycemia in STZ-diabetic rats may reverse the higher gene expression of opioid mu-receptor. These results suggest that hyperglycemia is responsible for increase of opioid mu-receptor in STZ-diabetic rats.
Cheng
J T
JT
The Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan 70101, R.O.C.
Liu
I M
IM
Chi
T C
TC
Tzeng
T F
TF
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000139:chemically induced / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006943:Hyperglycemia / Q000378:metabolism; D007275:Injections, Intravenous; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D008139:Loperamide / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009294:Narcotics / Q000494:pharmacology; D012333:RNA, Messenger / Q000819:agonists / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D013311:Streptozocin
D001786:Blood Glucose; D007328:Insulin; D009294:Narcotics; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; D013311:Streptozocin; D008139:Loperamide