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Alpha-melanocyte stimulating hormone (α-MSH) is known as a regulator of the blood glucose homeostasis and food intake. In the present study, the possible roles of α-MSH located in the spinal cord in the regulation of the blood glucose level were investigated in d-glucose-fed and immobilization stress (IMO) mouse models. We found in the present study that intrathecal (i.t.) injection with α-MSH alone did not affect the blood glucose level. However, i.t. administration with α-MSH reduced the blood glucose level in d-glucose-fed model. The plasma insulin level was increased in d-glucose-fed model and was further increased by α-MSH, whereas α-MSH did not affect plasma corticosterone level in d-glucose-fed model. In addition, i.t. administration with glucagon alone enhanced blood glucose level and, i.t. injection with glucagon also increased the blood glucose level in d-glucose-fed model. In contrasted to results observed in d-glucose-fed model, i.t. treatment with α-MSH caused enhancement of the blood glucose level in IMO model. The plasma insulin level was increased in IMO model. The increased plasma insulin level by IMO was reduced by i.t. treatment with α-MSH, whereas i.t. pretreatment with α-MSH did not affect plasma corticosterone level in IMO model. Taken together, although spinally located α-MSH itself does not alter the blood glucose level, our results suggest that the activation of α-MSH system located in the spinal cord play important modulatory roles for the reduction of the blood glucose level in d-glucose fed model whereas α-MSH is responsible for the up-regulation of the blood glucose level in IMO model. The enhancement of insulin release may be responsible for modulatory action of α-MSH in down-regulation of the blood glucose in d-glucose fed model whereas reduction of insulin release may be responsible for modulatory action of α-MSH in up-regulation of the blood glucose in IMO model.

Meglitinides (nateglinide and repaglinide) are widely used oral drugs for the treatment of type II diabetes mellitus. In the present study, the effects of meglinitides 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 30 μg of nateglinide and repaglinide for 10 min and then, mice were administered i.c.v. with KA (0.1 μg). 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 120 min after KA administration. We found that i.c.v. pretreatment with repaglinide attenuated the KA-induced neuronal cell death in CA3 region of the hippocampus and hyperglycemia. However, nateglinide pretreated i.c.v. did not affect the KA-induced neuronal cell death and hyperglycemia. In addition, KA administered i.c.v. caused an elevation of plasma corticosterone level and a reduction of the plasma insulin level. Furthermore, i.c.v. pretreatment with repaglinide attenuated KA-induced up-regulation of plasma corticosterone level. Furthermore, i.c.v. administration of repaglinide alone increased plasma insulin level and repaglinide pretreated i.c.v. caused a reversal of KA-induced hypoinsulinemic effect. Our results suggest that supraspinally administered repaglinide, but not nateglinide, exerts a protective effect against the KA-induced neuronal cells death in CA3 region of the hippocampus. The neuroprotective effect of repaglinide appears to be mediated by lowering the blood glucose level induced by KA.

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.

The possible involvement of glucocorticoid system in interleukin-1β (IL-1β)-induced nociception and the blood glucose level was studied in ICR mice. In the first experiment, mice were treated intrathecally (i.t.) with IL-1β (100 pg). Corticotrophin releasing hormone (CRH) mRNA (hypothalamus) and c-Fos mRNA (pituitary gland, spinal cord, and the adrenal gland) levels were measured at 30, 60 and 120 min after IL-1β administration. We found that i.t. injection with IL-1β increased CRH mRNA level in the hypothalamus. The IL-1β administered i.t. elevated c-Fos mRNA levels in the spinal cord, pituitary and adrenal glands. Furthermore, i.t. administration of IL-1β significantly increased the plasma corticosterone level up to 60 min. In addition, the adrenalectomy caused the reductions of the blood glucose level and pain behavior induced by IL-1β injected i.t. in normal and D -glucose-fed groups. Furthermore, intraperitoneal (i.p.) pretreatment with RU486 (100 mg/kg) attenuated the blood glucose level and pain behavior induced by IL-1β administered i.t. in normal and D -glucose-fed groups. Our results suggest that IL-1β administered i.t. increases the blood glucose level and pain behavior via an activation of the glucocorticoid system.

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 30 μg metformin, pioglitazone and rosiglitazone in d -glucose fed and streptozotocin-treated models, and blood glucose levels was measured at 30, 60 and 120 min 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.

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 60 min 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.

We studied the effects of supraspinally administered morphine on the expression of the hypothalamic pro-opiomelanocortin (POMC) gene and beta-endorphin. Mice were administered morphine intracerebroventricularly (i.c.v.) either once or 5 times for 5 days (once/day). A single morphine administration significantly increased the hypothalamic POMC gene and beta-endorphin expression at 2h after application in dose-dependent fashion; however, repeated morphine administration had no effect on the hypothalamic POMC gene and beta-endorphin expression. In the immunoblot and immunohistochemical study, the increase of beta-endorphin was observed in the arcuate nucleus of the hypothalamus. Moreover, the expressions of c-Fos, phosphorylated calcium/calmodulin-dependent protein kinase-IIalpha (pCaMK-IIalpha), and phosphorylated cAMP response element-binding protein (pCREB) were increased by a single i.c.v. morphine injection at various time points, but the expressions of phosphorylated extracellular signal-regulated protein kinase1/2 (pERK1/2) and phosphorylated IkappaB (pIkappaB) were not. We also found that the expressions of c-Fos, pCaMKIIalpha, and pCREB were co-localized with the POMC expression. Meanwhile, naloxone as well as muscimol and baclofen significantly attenuated the increases of the POMC gene expression induced by a single morphine administration. Furthermore, the pretreatment of muscimol and baclofen 10 min before morphine injection robustly attenuated the withdrawal behavior induced by a single morphine administration. These results imply that the hypothalamic POMC gene and beta-endorphin expression may play an important role in the development of an acute physical dependency of morphine. In that, GABAergic neurotransmission appear to be involved in the regulation of the hypothalamic POMC gene expression induced by supraspinal morphine administration.

Various doses of 3-isobutyl-1-methylxanthine (IBMX), a cAMP phosphodiesterase inhibitor, injected intrathecally (i.t.) or intracerebroventricularly (i.c.v.) alone did not show any antinociceptive effect. IBMX (0.01 to 1 ng) pretreatment i.t. for 10 min dose-dependently attenuated the inhibition of the tail-flick response induced by i.c.v. administered morphine (2 micrograms), beta-endorphin (1 microgram), and U50, 488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl] benzeocetamide), 60 micrograms. However, pretreatment with IBMX i.c.v. did not affect the inhibition of the tail-flick response induced by morphine, beta-endorphin, and U50, 488H administered i.c.v. Neither i.c.v. nor i.t. pretreatment with IBMX attenuated the inhibition of the tail-flick response induced by D-Pen2-D-Pen5-enkephalin (DPDPE; 10 micrograms) administered i.c.v. Our results suggest that spinal but not supraspinal cAMP phosphodiesterases are involved in mediating antinociception induced by morphine, beta-endorphin and U50, 488H administered supraspinally. However, neither spinal nor supraspinal cAMP phosphodiesterase is involved in mediating antinociception induced by DPDPE administered supraspinally.