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We examined the role of spinally located β-adrenergic receptors in the regulation of the blood glucose level. The intrathecal (i.t.) injections with dobutamine (β1-adrenergic receptor agonist) or terbutaline (β2-adrenergic receptor agonist) caused an elevation of the blood glucose level, whereas metoprolol (β1-adrenergic receptor antagonist) or butoxamine (β2-adrenergic receptor antagonist) did not. In addition, i.t. pretreatment with pertussis toxin (PTX) attenuated the hyperglycemic effect induced by dobutamine or terbutaline. Moreover, plasma insulin level was increased by dobutamine but not by terbutaline, and PTX reduced dobutamine-induced up-regulation of the plasma insulin level. Terbutaline significantly increased plasma corticosterone level, and PTX further enhanced terbutaline-induced corticosterone level. Furthermore, intraperitoneal (i.p.) pretreatment with hexamethonium- (a preganglionic blocker) attenuated dobutamine- and terbutaline-induced hyperglycemic effects. Our results suggest that activation of spinal β1- and β2-adrenergic receptors produces hyperglycemic effects in a different manner. Spinally located PTX-sensitive G-proteins appear to be involved in hyperglycemic effect induced by terbutaline. Furthermore, dobutamine- or terbutaline-induced hyperglycemia appears to be mediated through the spinal nerves. [ABSTRACT FROM AUTHOR]

5,7-Dihydroxytryptamine (5,7-DHT) is a neurotoxin which causes the depletion of serotonin. Moreover, the serotonergic system is the regulator of the blood glucose level. However, the role of centrally located serotonergic system in blood glucose regulation after D-glucose feed and immobilization (IMO) stress was not clearly characterized yet. Thus the present study was designed to examine the effect of 5,7-DHT administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) on the blood glucose level in D-glucose-fed and immobilization stress models. Mice were pretreated once i.c.v. or i.t. with 5,7-DHT (from 10 to 40 µg) for 3 days and D-glucose (2 g/kg) was fed orally. The blood glucose level was measured at 0, 30, 60 and 120 min after D-glucose feeding and immobilization stress initiation. We found that i.c.v. or i.t. pretreatment with 5,7-DHT attenuated the blood glucose level in both animal models. D-glucose feeding causes an increase in plasma insulin level, whereas the plasma corticosterone level was downregulated in the D-glucose-fed model. The i.c.v. or i.t. pretreatment with 5,7-DHT alone slightly increased the plasma corticosterone level. In addition, the i.c.v. or i.t. pretreatment with 5,7-DHT caused a reversal of the downregulation of plasma corticosterone level induced by D-glucose feeding, whereas immobilization stress causes an increase in plasma corticosterone and insulin levels. The i.c.v or i.t. pretreatment with 5,7-DHT attenuated the immobilization stress-induced plasma corticosterone and plasma insulin levels. Our results suggest that supraspinal and spinal depletion of serotonin appears to be responsible for the downregulation of blood glucose level in both D-glucose-fed and immobilization stress models. [ABSTRACT FROM AUTHOR]

Depression is more common among diabetes people than in the general population. In the present study, blood glucose change in depression animal model was characterized by various types of hyperglycemia models such as d -glucose-fed-, immobilization stress-, and drug-induced hyperglycemia models. First, the ICR mice were enforced into chronic restraint stress for 2 h daily for 2 weeks to produce depression animal model. The animals were fed with d -glucose (2 g/kg), forced into restraint stress for 30 min, or administered with clonidine (5 μg/5 μl) supraspinally or spinally to produce hyperglycemia. The blood glucose level in depression group was down-regulated compared to that observed in the normal group in d -glucose-fed-, restraint stress-, and clonidine-induced hyperglycemia models. The up-regulated corticosterone level induced by d -glucose feeding or restraint stress was reduced in the depression group while the up-regulation of plasma corticosterone level is further elevated after i.t. or i.c.v. clonidine administration in the depression group. The up-regulated insulin level induced by d -glucose feeding or restraint stress was reduced in the depression group. On the other hand, blood corticosterone level in depression group was up-regulated compared to the normal group after i.t. or i.c.v. clonidine administration. Whereas the insulin level in depression group was not altered when mice were administered clonidine i.t. or i.c.v. Our results suggest that the blood glucose level in depression group is down-regulated compared to the normal group during d -glucose-fed-, immobilization stress-, and clonidine-induced hyperglycemia in mice. The down-regulation of the blood glucose level might be one of the important pathophysiologic changes in depression. [ABSTRACT FROM AUTHOR]

DSP-4[ N -(2-chloroethyl)- N -ethyl-2-bromobenzylamine hydrochloride] is a neurotoxin that depletes norepinephrine. The catecholaminergic system has been implicated in the regulation of blood glucose level. In the present study, the effect of DSP-4 administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) on blood glucose level was examined in d -glucose-fed and restraint stress mice models. Mice were pretreated once i.c.v. or i.t. with DSP-4 (10–40 μg) for 3 days, and d -glucose (2 g/kg) was fed orally. Blood glucose level was measured 0 (prior to glucose feeding or restraint stress), 30, 60, and 120 min after d -glucose feeding or restraint stress. The i.c.v. or i.t. pretreatment with DSP-4 attenuated blood glucose level in the d -glucose-fed model. Plasma corticosterone level was downregulated in the d -glucose-fed model, whereas plasma insulin level increased in the d -glucose-fed group. The i.c.v. or i.t. pretreatment with DSP-4 reversed the downregulation of plasma corticosterone induced by feeding d -glucose. In addition, the d -glucose-induced increase in plasma insulin was attenuated by the DSP-4 pretreatment. Furthermore, i.c.v. or i.t. pretreatment with DSP-4 reduced restraint stress-induced increases in blood glucose levels. Restraint stress increased plasma corticosterone and insulin levels. The i.c.v. pretreatment with DSP-4 attenuated restraint stress-induced plasma corticosterone and insulin levels. Our results suggest that depleting norepinephrine at the supraspinal and spinal levels appears to be responsible for downregulating blood glucose levels in both d -glucose-fed and restraint stress models. [ABSTRACT FROM AUTHOR]

The effect of cholera toxin (CTX) or pertussis toxin (PTX) administered supraspinally on hippocampal neuronal cell death in CA3 region induced by kainic acid (KA) was examined in mice. After the pretreatment with either PTX or CTX intracerebroventricularly (i.c.v.), mice were administered i.c.v. with KA. The i.c.v. treatment with KA caused a neuronal cell death in CA3 region and PTX, but not CTX, attenuated the KA-induced neuronal cell death. In addition, i.c.v. treatment with KA caused an elevation of the blood glucose level. The i.c.v. PTX pretreatment alone caused a hypoglycemia and inhibited KA-induced hyperglycemic effect. However, i.c.v. pretreatment with CTX did not affect the basal blood glucose level and KA-induced hyperglycemic effect. Moreover, KA administered i.c.v. caused an elevation of corticosterone level and reduction of the blood insulin level. Whereas, i.c.v. pretreatment with PTX further enhanced KA-induced up-regulation of corticosterone level. Furthermore, i.c.v. administration of PTX alone increased the insulin level and KA-induced hypoinsulinemic effect was reversed. In addition, PTX pretreatment reduces the KA-induced seizure activity. Our results suggest that supraspinally administered PTX, exerts neuroprotective effect against KA-induced neuronal cells death in CA3 region and neuroprotective effect of PTX is mediated by the reduction of KA-induced blood glucose level. [ABSTRACT FROM AUTHOR]

The roles of α 2 -adrenergic receptors located in the spinal cord in the regulation of blood glucose levels were studied in imprinting control region (ICR) mice. Mice were treated intrathecally (i.t.) with clonidine or yohimbine, and the blood glucose levels were measured at 0, 30, 60 and 120 min after i.t. administration. The i.t. injection with clonidine caused a pronounced elevation of the blood glucose levels in a dose-dependent manner. Clonidine-induced hyperglycemic effect was dose-dependently attenuated by i.t. pretreatment with yohimbine. Furthermore, plasma insulin level was attenuated by clonidine, and yohimbine pretreatment reversed partially, but significantly, clonidine-induced down-regulation of the plasma insulin level. I.t. pretreatment with pertussis toxin (PTX) almost abolished the hyperglycemic effect induced by clonidine. PTX pretreatment reversed the induced down-regulation of the insulin level. In addition, i.t. pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) or intraperitoneal (i.p.) pretreatment with mifepristone, hexamethonium and 6-hydroxydopamine (6-OHDA) attenuated the hyperglycemic effect induced by clonidine. I.t. injected clonidine significantly increased plasma corticosterone level. The elevated blood glucose level induced by clonidine was significantly decreased in adrenalectomized (ADX) mice. Our results suggest that the α 2 -adrenergic receptors located in the spinal cord play important roles for the elevation of the blood glucose level. The hyperglycemic effect induced by clonidine appears to be mediated by a reduction of the plasma insulin level. In addition, glucocortioid system appears to be involved in clonidine-induced hyperglycemic effect. Furthermore, the clonidine-induced hyperglycemia appears to be mediated via activating the spinal nerves or peripheral sympathetic nervous system. [ABSTRACT FROM AUTHOR]

Abstract: Sulfonylureas are widely used oral drugs for the treatment of type II diabetes mellitus. In the present study, the effects of sulfonylureas administered supraspinally on kainic acid (KA)-induced hippocampal neuronal cell death and hyperglycemia were studied in ICR mice. Mice were pretreated intracerebroventricularly (i.c.v.) with 30μg of tolbutamide, glyburide or glipizide for 10min and then, mice were administered i.c.v. with KA (0.1μg). The neuronal cell death in the CA3 region in the hippocampus was assessed 24h after KA administration and the blood glucose level was measured 30, 60, and 120min after KA administration. We found that i.c.v. pretreatment with tolbutamide, glyburide or glipizide attenuated the KA-induced neuronal cell death in CA3 region of the hippocampus and hyperglycemia. In addition, KA administered i.c.v. caused an elevation of plasma corticosterone level and a reduction of the plasma insulin level. The i.c.v. pretreatment with tolbutamide, glyburide or glipizide attenuated KA-induced increase of plasma corticosterone level. Furthermore, i.c.v. pretreatment with tolbutamide, glyburide or glipizide causes an elevation of plasma insulin level. Glipizide, but not tolbutamide or glyburide, pretreated i.c.v. caused a reversal of KA-induced hypoinsulinemic effect. Our results suggest that supraspinally administered tolbutamide, glyburide and glipizide exert a protective effect against KA-induced neuronal cells death in CA3 region of the hippocampus. The neuroprotective effect of tolbutamide, glyburide and glipizide appears to be mediated by lowering the blood glucose level induced by KA. [Copyright &y& Elsevier]

Highlights: [•] The KA-induced hippocampal CA3 neuronal death was attenuated by repaglinide. [•] Repaglinide attenuated the elevation of the blood glucose level induced by KA. [•] Repaglinide attenuated KA-induced up-regulation of plasma corticosterone level. [•] KA-mediated reduction in insulin level was reversed by repaglinide injection. [ABSTRACT FROM AUTHOR]

Highlights: [•] I.t. with ghrelin caused an elevation of the blood glucose level. [•] I.t. pretreatment with YIL781 attenuated ghrelin-induced hyperglycemic effect. [•] Enhanced insulin level by ghrelin was reduced by i.t. pretreatment with YIL781. [•] I.t. pretreatment with GLP-1 did not affect ghrelin-induced hyperglycemia. [•] I.t. with ghrelin increased blood glucose level in d-glucose-fed model. [Copyright &y& Elsevier]

Highlights: [•] CRH and c-Fos mRNA level after i.t. IL-1β injection was enhanced. [•] The i.t. IL-1β injection significantly increased the plasma corticosterone level. [•] The blood glucose level and pain behavior were decreased in adrenalectomized mice. [•] The RU486 attenuated the blood glucose level and pain behavior induced by IL-1β. [ABSTRACT FROM AUTHOR]

The possible roles of gamma-amino butyric acid (GABA) receptors located in the spinal cord for the regulation of the blood glucose level were studied in ICR mice. We found in the present study that intrathecal (i.t.) injection with baclofen (a GABA receptor agonist; 1-10 μg/5 μl) or bicuculline (a GABA receptor antagonist; 1-10 μg/5 μl) caused an elevation of the blood glucose level in a dose-dependent manner. The hyperglycemic effect induced by baclofen was more pronounced than that induced by bicuculline. However, muscimol (a GABA receptor agonist; 1-5 μg/5 μl) or phaclofen (a GABA receptor antagonist; 5-10 μg/5 μl) administered i.t. did not affect the blood glucose level. Baclofen-induced elevation of the blood glucose was dose-dependently attenuated by phaclofen. Furthermore, i.t. pretreatment with pertussis toxin (PTX; 0.05 or 0.1 μg/5 μl) for 6 days dose-dependently reduced the hyperglycemic effect induced by baclofen. Our results suggest that GABA receptors located in the spinal cord play important roles for the elevation of the blood glucose level. Spinally located PTX-sensitive G-proteins appear to be involved in hyperglycemic effect induced by baclofen. Furthermore, inactivation of GABA receptors located in the spinal cord appears to be responsible for tonic up-regulation of the blood glucose level. [ABSTRACT FROM AUTHOR]

Abstract: Background: In the present study, the possible anti-diabetic action of biguanide and thiazolidinediones administered supraspinally or spinally was studied in ICR mice. Methods: Mice were intracerebroventricular (i.c.v.) or intrathecal (i.t.) treated with 20 or 30μg metformin, pioglitazone and rosiglitazone in d-glucose fed and streptozotocin-treated models, and blood glucose levels was measured at 30, 60 and 120min after i.c.v. or i.t. administration. Results: We found that i.c.v. injection with metformin or rosiglitazone slightly attenuated the blood glucose level in d-glucose fed model, whereas pioglitazone showed no effect on the blood glucose level in d-glucose fed model. The i.t. administration with metformin, pioglitazone or rosiglitazone did not alter the blood glucose level in d-glucose fed model. We also assessed the possible roles of biguanide and thiazolidinedione in the regulation of the blood glucose level in streptozotocin-treated model. We found in the present study that i.c.v. or i.t. administration with metformin caused a pronounced attenuation of the blood glucose level in streptozotocin-treated model. However, rosiglitazone administered i.c.v. did not affect the blood glucose level in streptozotocin-treated model. Conclusions: Our results suggest that the anti-diabetic actions of metformin and rosiglitazone appear to be mediated via the brain regions as revealed in d-glucose fed animal model. Furthermore, metformin administered supraspinally or spinally may be effective for treating type I diabetes mellitus as revealed in streptozotocin-treated mouse model. [Copyright &y& Elsevier]

Abstract: The relationship between interleukin-1β (IL‐1β)‐induced nociception and the blood glucose level was studied in ICR mice. We found in the present study that intrathecal (i.t.) injection of IL‐1β increased pain behavior. In addition, i.t. IL‐1β injection caused an elevation of the blood glucose level. The time‐course study showed that maximal blood glucose level was observed 30 and 60min after i.t. IL‐1β administration. Furthermore, i.t. injection of IL‐1β enhanced the blood glucose level when mice were orally fed with d‐glucose. The i.t. administration of IL‐1β antagonist (AF12198) inhibited the hyperglycemia and pain behaviors induced by IL‐1β. We found in the present study that adrenal tyrosine hydroxylase (TH) mRNA level was also increased by i.t. IL‐1β injection. Furthermore, intraperitoneal (i.p.) pretreatment with phentolamine (an α1‐adrenergic blocker) or yohimbine (an α2‐adrenergic blocker) significantly attenuated the blood glucose level and pain behavior induced by IL‐1β administered i.t. However, the blood glucose level and pain behavior were not affected by butoxamine (a β2-adrenergic blocker), whereas metoprolol (a β2-adrenergic blocker) enhanced IL‐1β-induced blood glucose level and pain behavior in mice fed with d‐glucose. However, its effect was not statistically significant. Our results suggest that IL‐1β administered i.t. increases the blood glucose level via an activation of α adrenergic nervous system. [Copyright &y& Elsevier]

Effects of histamine receptors agonists or antagonists administered centrally (supraspinally or spinally) on immobilization stress-induced blood glucose levels were studied in Institute for Cancer Research mice. Mice were pretreated intracerebroventricularly (i.c.v.) or intrathecally (i.t.) with histamine (H1, H2, H3 and H4) receptor agonists or antagonists 10 min prior to immobilization stress (IMO) stimulation for 30 min. We found that the increased blood glucose level induced by IMO was attenuated by the i.c.v. pretreatment withα-methylhistamine (H3 agonist). However, H3 antagonist, H1, H2 and H4 receptor agonists and antagonists did not affect the blood glucose level. Also, i.t. pretreatment withα-methylhistamine or VUF 8430 attenuated the increased blood glucose level induced by IMO. In addition, cetirizine and carcinine enhanced the increased blood glucose level induced by IMO. However, the blood glucose level was not affected by H1 and H2 receptor agonists, H2 and H4 receptor antagonists. Corticosterone and insulin levels were also measured inα-methylhistamine (i.c.v or i.t) and with VUF 8430, carcinine and cetirizine (i.t.) treated group. We found that the corticosterone level was increased only by i.t treatment withα-methylhistamine, whereas the insulin level was attenuated by i.c.v or i.t. treatment withα-methylhistamine and i.t treatment with VUF 8430, carcinine and cetirizine. Our results suggest the active involvement of histamine receptor in blood glucose regulation in IMO. [ABSTRACT FROM AUTHOR]