Effects of Glucose and Diabetes on Binding of Naloxone and Dihydromorphine to Opiate Receptors in Mouse Brain

Abstract

The effects of glucose and diabetes on the high-affinity lofentanil-displaceable opiate-receptor binding in mouse brain membranes were studied to determine if the attenuation of opiate actions by hyperglycemia previously observed in our laboratory was due to a modification of receptor affinity or number. With membranes from normal ICR mice, glucose (100-400 mg/dl) caused small but significant concentration-dependent decreases in receptor affinities for [3H]naloxone and [3H]dihydromorphine, both in the absence and presence of 20 mM NaCl, without changing the maximum number of binding sites. Fructose and the nonmetabolizable sugar 3-O-methylglucose had intermediate effects on naloxone affinity in the presence of NaCl that were not significantly different from control or from the effect of glucose. Similar results were obtained with brain membranes from streptozocin-induced diabetic mice. The binding affinity for [3H]naloxone in the presence of NaCl was not affected by the induction of diabetes in ICR mice via streptozocin or in spontaneously diabetic (db/db) C57BL/KsJ mice compared with their nondiabetic (m+/m+) littermates. These results indicate that the previously observed attenuation of opiate effects by glucose may be partly due to a glucose-induced decrease in opiate-receptor affinity. However, the much greater attenuation of morphine by fructose in vivo cannot be explained by this mechanism.

Effects of Acute and Chronic Hyperglycemia on Morphine-Induced Inhibition of Gastrointestinal Transit in Mice

“…Hence, glucose-induced modulation of the peripheral mechanism(s) could be consid ered as the possible basis for the augmented anti-transit effect of morphine observed in the acute hyperglycemic groups. Glucose has been shown to produce a concentration-de pendent decrease in opiate receptor binding affinity in vitro [7], Furthermore, the po tency of normorphine to inhibit electrically stimulated guinea-pig ileum in vitro has been shown to be reduced by increasing the concentration of glucose in the bath [6]. However, the present study indicates that in in vivo acute hyperglycemia augments the inhibitory effect of morphine on gut transit while chronic hyperglycemia fails to modify the response of morphine.…”

“…Some in vivo [4,5] and in vitro [6] experiments sup port the hypothesis that the decreased sensi tivity to morphine in experimental models of diabetes is primarily due to the hypergly cemia associated with diabetes. However, some recent in vivo [unpublished data, Ra mabadran et al, 1988] and in vitro results [7] contradict this hypothesis. Furthermore, a dichotomy in the modulation of hypother mic response to morphine in acute versus chronic hyperglycemia has also been observed [8].…”

Opiate-mediated inhibition of calcium signaling is decreased in dorsal root ganglion neurons from the diabetic BB/W rat.

“…Both increased and decreased antinociceptive responses to opiate agonists have been described in diabetes mellitus (13). The effect of diabetes on opiate-mediated inhibition of tail-flick and other avoidance responses may be related to the degree of hyperglycemia (25,26). Differential effects of opiates have been reported in the central and peripheral nervous system, with su- ] i response to KClmediated depolarization in calcium-containing and calcium-free medium for eight neurons.…”

“…Decreased opiate receptor expression could explain the loss of opiate responsiveness in diabetes, and impaired vagal transport of opiate receptors has been demonstrated in streptozotocin-induced diabetic rats (14). However, elevated beta endorphin binding sites on muscle have been documented in the type II obese diabetic mouse model (29), and neuronal opiate receptor binding in the brain is not altered in spontaneously diabetic or streptozotocin-induced diabetic rats (30). Alternatively, altered opiate receptor coupling to ion channels might be present in diabetes.…”

Hippocampal acetylcholine release during memory testing in rats: augmentation by glucose.

“…Glucose reverses decreases in memory performance and hippocampal ACh output induced by morphine, an opiate agonist (19,23,24). Furthermore, an increase in blood glucose levels reduces the affinity of opiatereceptor binding (39), suggesting that glucose may act functionally as an opioid antagonist. These results suggest that the increase in ACh release following glucose treatment may be through indirect actions.…”