Hyperglycaemia as a factor affecting kappa-opiate agonist-induced inhibition of the gastrointestinal transit in mice

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.