Glibenclamide's action in the hypothalamus alters peripheral glucose homeostasis.

Bilateral injections of 0.2 nmol of glibenclamide, targeted at the ventromedial hypothalamus of albino rats, significantly impaired recovery of blood glucose levels following insulin-induced hypoglycemia (P=0.0026). Similar injections of 0.2 and 2.0 nmol glibenclamide reduced blood glucose by 23.6 and 40.8 mg%, respectively, in otherwise untreated rats (P<0.01 and P<0.001). Intravenous injection of these doses of the drug did not lower blood glucose. The results support the hypothesis that K(ATP)(+) channels within the hypothalamus serve a counterregulatory function in the maintenance of peripheral glucose levels.

Glucose feeding exacerbates parathion-induced neurotoxicity.

Excessive dietary intake of sugars could alter various biotransformation processes and the pharmacological and toxicological properties of numerous xenobiotics. In the present study, the effects of glucose supplementation were examined on the neurotoxicity of the organophosphorus (OP) pesticide parathion (PS) and its active metabolite, paraoxon (PO), a potent inhibitor of acetylcholinesterase (AChE). Rats (n = 6-12/treatment group) were given free access to tap water or 15% glucose (w/v) in tap water beginning 7 d prior to OP toxicant exposure. Food, caloric intake, and body weight were measured daily. Animals were challenged with either PS (4.5, 9, or 18 mg/kg, sc) or PO (0.3 0.5, or 0.7 mg/kg, sc) and clinical signs of neurotoxicity (i.e., autonomic dysfunction, involuntary movements) were recorded daily for the following 13 d. Glucose feeding was associated with a dramatic drop (approximately 50%) in feed intake and an increase (approximately 20% in total caloric consumption over the 7 d prior to OP exposure. Functional toxicity associated with PS exposure was increased in glucose-fed (GF) rats, but the glucose diet had no apparent effect on clinical signs of toxicity following PO treatment. Glucose feeding increased the magnitude of AChE inhibition in the frontal cortex and plasma at lower dosages (i.e., 4.5 and 9 mg/kg) 3 d following PS treatment. Time-course studies (3, 7, and 11 d after PS exposure, 18 mg/kg, sc) indicated significantly greater brain and plasma AChE inhibition in glucose-fed animals at later time points. In contrast, glucose feeding had no effect on the degree of AChE inhibition following PO exposure. Neither liver microsomal oxidative desulfuration of PS, nor liver or plasma paraoxonase, nor liver or plasma carboxylesterase activities were measurably affected by glucose feeding. Downregulation of muscarinic receptors 7 d after PS exposure (18 mg/kg, sc) was more extensive in GF rats. It is postulated that excessiveglucose consumption decreases the intake of other dietary components, in particular amino acids, limiting the de novo synthesis of AChE and consequent recovery of synaptic transmission. Due to the shorter duration of inhibition following PO exposure, sponta neous reactivation of AChE may be more important than de novo protein synthesis in recovery of function, and thus with the effects of glucose feeding on its toxicity. Individuals that derive a large proportion of their calories from sugars may be at higher risk of acute toxicity from organophosphorus pesticides such as PS.

The Effect of Centrally Administered Glibenclamide, Tolbutamide and Diazoxide on Feeding in Rats.

While there are many theories on the control of feeding behavior that emphasize a role for energy substrates and their metabolism, the mechanism that couples changes in energy substrate supply and metabolism to alterations in food intake remains unclear. The purpose of the present project was to investigate the possibility that central ATP-sensitive potassium (KATP(+)) channels may serve as integrators between cellular energetics and alterations in neuronal activity that control feeding, such that pharmacologic manipulation of the channels would result in alterations in feeding behavior. Intracerebroventricular (ICV) injections of the KATP(+) channel blocker glibenclamide significantly increased feeding in fasted and fed male Sprague-Dawley rats. Likewise, the first generation sulfonylurea, tolbutamide, also increased feeding. ICV injection of the KATP(+) channel opener, diazoxide, modestly inhibited feeding. These results suggest that central KATP(+) channels may be involved in the regulation of feeding behavior.

ATP-sensitive K(+) Channels in the Regulation of Feeding Behavior: A Hypothesis.

In this paper we present a relatively narrow view of a wide body of literature, the elements of which share two featuresin common: an effect on food intake, and a relationship to an ATP-sensitive K(+) channel. With only sparse direct evidence available, we propose and provide circumstantial evidence supporting the hypothesis that ATP-sensitive potassium channels are ubiquitously relevant molecular integrators of energy balance, playing a role in numerous neuronal and hormonal systems involved in the maintenance of both energy intake and energy expenditure. Further, we focus on a few of the latest findings in this area which suggest that out hypothesis, while seemingly tenable, may involve process with unexpected levels of complexity.

Quinpirole-induced alterations of tail temperature appear as hyperalgesia in the radiant heat tail-flick test.

Several reports in the recent literature argue both for and against the importance of alterations of tail-temperature in the outcome of the tail-flick test. The data we present here support the assertion that drug-induced changes of tail-temperature may have a highly significant effect on tail-flick latency independent of drug-induced changes in nociception. We previously reported that peripherally administered injections of the dopamine agonist, quinpirole, produce significant reductions in the latency of response in the tail-flick test. This present work confirms our earlier findings; however, it indicates that the apparent hyperalgesia is an artifactual function of quinpirole-induced increases in tail temperature. Quinpirole (0.1-1.0 mg/kg I.P.) produced significant (p < 0.001), dose-dependent, and highly correlated increases in tail temperature and decreases in tail-flick latency 15 min following injection. When controls for the change in tail temperature were applied, there was no distinguishable effect of the drug on tail-flick latencies. Sixty minutes following the administration of quinpirole there was no observable effect of the drug on either tail-temperature or tail-flick latency. The results of this study indicate that a) peripherally administered quinpirole has no effect on nociception as measured in the tail-flick test apart from its ability to alter tail temperature; and b) alterations in tail temperature may significantly alter the outcome of the tail-flick test.

Dietary Sucrose Lowers Nociceptive Latencies Independently of Thermogenic Effects.

Previous reports indicate that chronic sucrose feeding produces a significant reduction in the latency of response in the radiant heat tail-flick test. Other earlier studies have shown a relationship between tail-skin temperature and tail-flick latency, while others yet have shown an increase in tail-skin temperature following sucrose feeding. Together these previous findings suggest the possibility that dietary-induced alterations in nociceptive latencies occur as an artifact secondary to diet-related changes in tail-skin temperature. The data presented in this study show that chronic sucrose feeding significantly increased tail-skin temperature (p < 0.0001) and decreased tail-flick latency (p < 0.0001) with significant correlations between tail-skin temperatures and tail-flick latencies in both the control and sucrose fed groups. However, while the slopes of the regression lines were similar for both groups, the elevations of the lines were significantly different (p = 0.0068) suggesting a dietary impact on nociceptive thresholds independent of the temperature effect. The data were also subjected to a previously reported temperature-correction procedure and comparisons in the methods of data analysis are discussed.

Cadmium disposition in the earthworm Eisenia fetida.

The disposition of cadmium was examined in the earthworm Eisenia fetida using two exposure media, filter paper, and artificial soil. Uptake and elimination rates were estimated to be 0.03039 and 0.00895 hr-1, respectively, for 1.25 micrograms Cd/cm2 filter paper exposure and 0.00512 and 0.00029 hr-1, respectively, for 10 micrograms Cd/g artificial soil exposure. The distribution of cadmium was examined using whole body autoradiography, tissue distribution, and subcellular localization. Cadmium tissue distribution was exposure-dependent, while cadmium subcellular localization apparently was not exposure-dependent. Acid-soluble thiol levels, examined as an index of cadmium exposure, were too variable in nonexposed earthworms to serve as an indicator of cadmium exposure.

Reduction of food intake and morphine analgesia by central glybenclamide.

Previous research has indicated the presence of a reciprocal relationship between food intake and opioid-mediated analgesia. We believe the cellular candidate most likely acting as a common mediator of both ingestive and nociceptive behaviors is the ATP-sensitive K+ channel (K+ATP). This ion channel appears to be opened by mu and delta 1 opioid receptor agonists in the service of analgesia, and closed as cellular ATP availability rises. To further examine the role of the K+ATP in the relationship between feeding and opioid function, we administered 80 nmol of glybenclamide (a K+ATP antagonist) to male SD rats via the lateral ventricle. Chow consumption in the treated animals was significantly reduced over the following 48 h (F = 2.62, p < 0.013), with the peak effect (78% of control) occurring at 6 h. In the tail-flick test, 4 mg/kg morphine sulfate provided analgesia of 42.38 +/- 8.4% and 18.89 +/- 7.67% in vehicle and treated animals, respectively (p < 0.05, n = 8/group, one-tailed t-test). These results support the hypothesis that food intake and analgesia are reciprocally modulated through activity at the K+ATP.

Evidence of hyperglycemic hyperalgesia by quinpirole.

Male albino rats were tested for antinociception following injections (IP) with saline, quinpirole (Quin) (1 mg/kg), morphine sulfate (M.S.) (5 mg/kg), or both Quin and M.S. (1 mg/kg and 5 mg/kg, respectively). Quin reduced and M.S. increased tail-flick latency as compared to controls. Tail-flick latencies of the animals injected with both drugs were significantly reduced as compared M.S. alone. Quin increased blood glucose levels by 96 percent, as compared to saline controls. In competitive binding studies Quin displaced 3H-DAGO (IC50 = 29.8 microM). CD-1 mice demonstrated a naloxone-reversible analgesia following ICV Quin (100 micrograms). These data are consistent with the hypothesis that the hyperglycemic effects of Quin attenuate M.S. analgesia while the antinociceptive effects of Quin may be mediated through opioid receptors.

Discontinuation of sustained sucrose-feeding aggravates morphine withdrawal.

Sprague-Dawley rats were allowed ad lib access to a 20% sucrose solution in addition to their normal diet to investigate the relationship between the prolonged consumption of a high carbohydrate diet and opioid function as evidenced by opioid dependence and withdrawal. Morphine dependence, assayed by tailflick, was induced, followed by naloxone-precipitated withdrawal, gauged by weight loss. Sucrose-fed animals developed lowered pain thresholds prior to dependence induction relative to those of control animals, but failed to exhibit any differences from controls in the development of dependence. Weight loss during withdrawal was increased by the discontinuation of sustained sucrose-feeding. In addition, the induction of dependence first decreased, then increased the animals' preference for sucrose. It is concluded that changes in opioid function caused by sustained sucrose-feeding are insufficient to affect the development of tolerance to morphine analgesia, but do aggravate the symptoms of precipitated withdrawal when access to sucrose is denied prior to the injection of naloxone.

Continuous sucrose feeding decreases pain threshold and increases morphine potency.

Although an opioid-mediated mechanism appears to be involved in the alteration of pain perception during feeding behavior, little is known about macronutrient effects on nociception. In this report we show that prolonged sucrose feeding alters responsiveness to painful stimuli and the analgesic potency of morphine. Male Sprague-Dawley rats maintained on ad lib laboratory chow with continuous access to a 20% sucrose solution displayed a significant decrease in tail-flick latency as early as 20 hours after introduction of the sucrose. The differences in pain threshold were naloxone sensitive. After 25 days on the diet, morphine sulfate, 8 mg/kg administered IP, proved to be significantly more potent in the sucrose-fed animals. The results indicate that sucrose feeding alters endogenous opioid-mediated nociception.

Relationships between sustained sucrose-feeding and opioid tolerance and withdrawal.

This study examines the effect of sustained sucrose consumption on the development of tolerance to morphine analgesia (20 mg/kg IP injections) and subsequent, naloxone-precipitated withdrawal (2 mg/kg IP). Food intakes are also measured. Sprague-Dawley rats were allowed ad lib access to a 20% sucrose solution in addition to their normal diet. Pain thresholds and intakes were monitored for two weeks, then morphine tolerance was induced, followed by precipitated withdrawal. Tolerance was assayed by the tailflick method, and withdrawal was gauged by weight loss. The animals given access to sucrose developed lowered pain thresholds prior to tolerance induction relative to those of control animals, but they failed to exhibit any differences from controls in tolerance development of severity of withdrawal. The induction of tolerance first decreased, then increased sucrose consumption and steadily decreased chow consumption. Naloxone-precipitated withdrawal decreased chow consumption, but failed to affect the ingestion of the sucrose solution. It is concluded that changes in opioid function caused by sustained sucrose-feeding are insufficient to affect the development of tolerance to morphine analgesia; however, tolerance induction biphasically alters sucrose consumption.

Decreased [3H]-naloxone binding and elevated dynorphin-A(1-8) content in Zucker rat brain.

We have previously reported that female obese Zucker rats are hypersensitive to painful stimuli and are resistant to the analgesic effects of morphine. In continuation we hypothesized that these phenomena are possibly the result of diminished population of opioid receptors, or an overabundance of dynorphin interfering with morphine analgesia. We now report that female obese Zucker rats have decreased concentrations of mu opioid receptors in whole brain and elevated levels of Dynorphin A(1-8) (DYN) in a brain area known to be associated with responses to nociceptive stimuli.

Nociception and opioid-induced analgesia in lean (Fa/-) and obese (fa/fa) Zucker rats.

Previous research indicates a possible interrelationship between the endogenous opioids (EO), nociception and food-intake. We therefore considered the hyperphagic obese Zucker rat a good candidate for abnormal responses to nociceptive stimuli. Pairs of lean and obese sisters were tested for latency of response to nociceptive stimuli by tail-flick and tail-pinch methods. Obese rats exhibited shorter latencies in each test, (tail-flick, p less than 0.05 and tail-pinch, p less than 0.001). Dose/response curves for morphine analgesia indicate that morphine is less potent in obese than in lean rats (ED50's = 4.87 +/- 0.62 mg/kg and 3.12 +/- 0.41 mg/kg respectively, p less than 0.05). These data suggest a defect in the EO systems of obese Zucker rats.