u-50488 and Hyperglycemia

Opioid and its receptors play important roles in glucose homeostasis. However, few reports were available for the study of κ-opioid receptor in glucose regulation. In our study, we found that the blood glucose of diabetic mice dropped significantly following the treatment with U50,488H (a selective κ-opioid receptor agonist). This phenomenon was time-dependent and associated with the coincident alteration of Glut4 translocation in the skeleton muscles. U50,488H increased the serum adiponectin, but not serum insulin in diabetic mice. U50,488H increased the AdipoR1 expression at both mRNA and protein levels. It also promoted AMPK phosphorylation and Glut4 translocation. All these effects were abolished by nor-BNI (a selective κ-opioid receptor antagonist). These findings suggest that activation of κ-opioid receptor reduces hyperglycemia in streptozotocin-induced diabetic mice. This effect is associated with the translocation of Glut4 and might be relevant to increased adiponectin, AdipoR1, and AMPK phosphorylation.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adiponectin; AMP-Activated Protein Kinases; Analgesics, Non-Narcotic; Animals; Blood Glucose; Blotting, Western; Diabetes Mellitus, Experimental; Gene Expression; Glucose Transporter Type 4; Homeostasis; Hyperglycemia; Insulin; Male; Mice, Inbred BALB C; Naltrexone; Narcotic Antagonists; Phosphorylation; Protein Transport; Receptors, Adiponectin; Receptors, Opioid, kappa; Reverse Transcriptase Polymerase Chain Reaction

The effects of mu and kappa opiate agonists were assessed on the pupillary size in normoglycemic and hyperglycemic conditions in mice. The mu agonists used were, morphine (10, 30 and 100 mg/kg), fentanyl (50, 100 and 150 micrograms/kg) and sufentanil (5, 10 and 20 micrograms/kg). The highly selective kappa opiate agonists used were, U-50488H and U-69593 (30 mg/kg). Chronic hyperglycemia was induced by streptozotocin injection (200 mg/kg i.p) 7-8 days before the experiment. Acute hyperglycemia was induced by intraperitoneal glucose (5 g/kg i.p) injection at the time of subcutaneous injection of opiates. In the normoglycemic mice, the mu agonists produced significant mydriasis (P less than 0.05), while kappa agonists had no effect on the pupil. However, both acute and chronic hyperglycemic condition did not affect the mydriatic ratio of the mu opiate agonists. These results indicate that mu opiate receptors induce mydriasis in mice and suggest that the hyperglycemia is not the mechanism involved in the opiate induced mydriasis in mice. With the dose of kappa agonists used, the involvement of kappa receptors in the pupillary effects in mice were not clear. These results support the hypothesis that hyperglycemia is not the primary mechanism for the altered sensitivity of opiates in the animal models of diabetes.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzeneacetamides; Blood Glucose; Fentanyl; Half-Life; Hyperglycemia; Male; Mice; Morphine; Narcotics; Pupil; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

The effects of highly selective kappa-opiate agonists were assessed on the gastrointestinal motility in normoglycaemic and hyperglycaemic conditions in mice. Chronic hyperglycaemia was induced by streptozocin injection (200 mg kg-1 i.p.), 7-8 days before the experiment. Acute hyperglycaemia was induced by glucose injection (5 g kg-1 i.p.) at the time of opiate administration. The kappa-opiate agonists, U-50488H and U-69593 (1, 3 and 10 mg kg-1) were injected (i.p.) just before the charcoal meal. The animals were killed 45 min later and the distance travelled by the test meal was measured. In the normoglycaemic mice, both kappa-agonists significantly (P less than 0.05) inhibited the meal transit and this effect was significantly (P less than 0.05) augmented in acute hyperglycaemic animals. However, in chronic hyperglycaemic animals U-50488H failed to inhibit the charcoal meal transit, while U-69593 produced anti-transit effect comparable to that observed in normoglycaemic mice. These results demonstrate that kappa-opiate agonists produce anti-transit effects in mice that these effects are enhanced during acute hyperglycaemia. The disparity of anti-transit effects of kappa-opiate agonists in acute vs chronic hyperglycaemia supports the hypothesis that elevated glucose levels are not the primary mechanism for the altered response to opiates observed in the experimental models of diabetes.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzeneacetamides; Blood Glucose; Charcoal; Diabetes Mellitus, Experimental; Gastrointestinal Transit; Hyperglycemia; Male; Mice; Narcotics; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa