Plasma Glucose–Lowering Effect of Tramadol in Streptozotocin-Induced Diabetic Rats

Cheng, Juei‐Tang; Liu, I-Min; Chi, Tzong‐Cherng; Tzeng, Thing-Fong; Lu, Feng-Hwa; Chang, Chih Jen

doi:10.2337/diabetes.50.12.2815

Cited by 108 publications

(132 citation statements)

References 32 publications

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“…A brain site of opioid action is suspected (24,39,40). As an alternative, a direct peripheral action might be considered, although the presence of the MOR in liver and skeletal muscle remains poorly documented (41)(42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

Resistance to Diet-Induced Obesity in μ-Opioid Receptor–Deficient Mice

et al. 2005

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Using pharmacological tools, a role for opioid receptors in the regulation of food intake has been documented. However, the involvement of specific receptor subtypes remains questionable, and little information is available regarding a role for opioid receptors in energy metabolism. Using adult male mice lacking the -opioid receptor (MOR) gene (MOR ؊/؊ ), we show that the MOR is not essential for the maintenance of normal levels of ad libitum food intake but does modulate the efficiency of energy storage during high-fat diets through the regulation of energy partitioning. When fed a regular diet, MOR ؊/؊ mice displayed only subtle alterations in energy homeostasis, suggesting a relative overuse of fat as a fuel source in the fed state. When fed a high-fat diet, MOR ؊/؊ mice were resistant to obesity and impaired glucose tolerance, despite having similar energy intake to wild-type mice. This resistance to obesity was associated with a strong induction of the expression of key mitochondrial enzymes involved in fatty acid oxidation within skeletal muscle. This metabolic role of the MOR, which is consistent with the properties of a "thrifty gene," suggests that the MOR pathway is a potential target for pharmacological intervention in the treatment of obesity associated with the intake of fatty diets. Diabetes 54: 3510 -3516, 2005 T he endogenous opioid system encompasses cloned receptor populations (, ␦, and ) and ligands (␤-endorphin, the enkephalins, and the dynorphins). Extensive work indicates that the opioid system plays a role in the regulation of appetite. Opioid receptors and peptides are expressed in sites of the central nervous system that play a role in regulating feeding behavior, and pharmacological experiments using opioid receptor ligands show that agonists promote eating and antagonists decrease food intake, at least in the short term (1-3). Numerous pharmacological studies indicate that opioids also play a role in modulating the rewarding effects of food (3-5). In contrast, little information suggests that opioids have a role in energy metabolism (6 -8).The need to establish the specific role of the opioid receptors in energy homeostasis has led to studies using putative specific opioid receptor ligands or, more recently, antisense probes directed against specific exons of opioid receptor genes (3,9). Pharmacological studies suggest that the and pathways are part of an interconnected brain network and participate in the orexigenic effect of several peptides that regulate food intake (10 -13). However, the interpretation of these data is complicated by our poor knowledge of the in vivo selectivity of ligand-receptor interactions that have been established in vitro (9,14).Recent studies conducted in mutant mice null for the opioid receptors have complemented pharmacological approaches and clarified the role of each receptor in nociception, anxiety, and drug abuse (14). To further define the role of the -opioid receptor (MOR) pathway in energy homeostasis, we characterized mice lacking the MOR gene ...

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Section: Discussionmentioning

confidence: 99%

Resistance to Diet-Induced Obesity in μ-Opioid Receptor–Deficient Mice

et al. 2005

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“…Our previous reports (Liu et al, 1999a;Cheng et al, 2001b, 2002) indicated that opioid -receptors participated in the regulation of glucose metabolism in an insulin deficient state. Endogenous ␤-endorphin has physiological activities that are mediated by opioid -receptors (Goldstein, 1987;Pasternak, 1993).…”

Section: Discussionmentioning

confidence: 96%

“…We have previously demonstrated that endogenous ␤-endorphin via the activation of opioid receptor is a positive regulator in the glucose use and a negative modulator in hepatic gluconeogenesis in the insulin-deficient state (Liu et al, 1999a;Cheng et al, 2001bCheng et al, , 2002. Thus, we used opioid -receptor antagonists to clarify the role of this receptor in isoferulic acid-induced changes in gene expression associated with glucose metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies (Liu et al, 1999a;Cheng et al, 2001bCheng et al, , 2002 have shown that activation of opioid -receptors by either exogenous ␤-endorphin or chemical agents, such as loperamide or tramadol, might improve glucose homeostasis in diabetic rats in the absence of insulin. Also, activation of ␣ 1 -adrenoceptors in adrenal medulla by phenylephrine might enhance the secretion of ␤-endorphin from the rat adrenal gland (Cheng et al, 2001c).…”

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confidence: 99%

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Mediation of β-Endorphin by Isoferulic Acid to Lower Plasma Glucose in Streptozotocin-Induced Diabetic Rats

Liu¹,

Chen²

2003

J Pharmacol Exp Ther

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We investigated the mechanism(s) by which isoferulic acid lowers plasma glucose levels in streptozotocin-induced diabetic rats (STZ-diabetic rats). In STZ-diabetic rats, isoferulic acid dose dependently lowered plasma glucose concentrations and increased plasma ␤-endorphin-like immunoreactivity (BER). Both of these effects of isoferulic acid were abolished by pretreatment of rats with tamsulosin or 2-[2,6-dimethoxyphenoxyethyl]aminomethyl-1,4-benzodioxane hydrochloride (WB 4101) at doses sufficient to block ␣ 1 -adrenoceptors. Also, isoferulic acid enhanced BER release from isolated rat adrenal medulla in a concentration-dependent manner that could be abolished by treatment with ␣ 1 -adrenoceptor antagonists. Moreover, bilateral adrenalectomy in STZ-diabetic rats eliminated the activities of isoferulic acid, including the plasma glucose-lowering effect and the plasma BER-elevating effect. Naloxone and naloxonazine inhibited the plasma glucose-lowering activity of isoferulic acid at doses sufficient to block opioid -receptors. In contrast with the effect in wild-type diabetic mice, isoferulic acid failed to lower plasma glucose levels in opioid -receptor knockout diabetic mice. Treatment of STZ-diabetic rats with isoferulic acid three times in 1 day resulted in an increase in the expression of the glucose transporter subtype 4 form in soleus muscle. This effect was blocked by ␣ 1 -adrenoceptor or opioid -receptor antagonists. The reduction of elevated mRNA or protein level of hepatic phosphoenolpyruvate carboxykinase was also impeded in the same groups of STZ-diabetic rats. In conclusion, our results suggest that isoferulic acid may activate ␣ 1 -adrenoceptors to enhance the secretion of ␤-endorphin, which can stimulate the opioid -receptors to increase glucose use or/and reduce hepatic gluconeogenesis, resulting in a decrease of plasma glucose in STZ-diabetic rats.

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“…Chemical agents such as loperamide and tramadol decreased plasma glucose via activation of opioid μ-receptors in a type 1 diabetes rat model [5,6]. Insulin resistance is described as the reduced response of peripheral tissues to insulin [7].…”

Section: Introductionmentioning

confidence: 99%

Activation of opioid μ-receptors by loperamide to improve interleukin-6-induced inhibition of insulin signals in myoblast C2C12 cells

Tzeng

Liu²

2005

Diabetologia

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Aims/hypothesis: This study investigated the role of opioid μ-receptor activation in the improvement of insulin resistance. Methods: Myoblast C 2 C 12 cells were cultured with IL-6 to induce insulin resistance. Radioactive 2-deoxyglucose (2-DG) uptake was used to evaluate the effect of loperamide on insulin-stimulated glucose utilisation. Protein expression and phosphorylation in insulinsignalling pathways were detected by immunoblotting. Results: The insulin-stimulated 2-DG uptake was reduced by IL-6. Loperamide reversed this uptake, and the uptake was inhibited by blockade of opioid μ-receptors. Insulin resistance induced by IL-6 was associated with impaired expression of the insulin receptor (IR), IR tyrosine autophosphorylation, IRS-1 protein content and IRS-1 tyrosine phosphorylation. Also, an attenuated p85 regulatory subunit of phosphatidylinositol 3-kinase, Akt serine phosphorylation and the protein of glucose transporter subtype 4 were observed in insulin resistance. Loperamide reversed IL-6-induced decrement of these insulin signals. Conclusions/interpretation: Opioid μ-receptor activation may improve IL-6-induced insulin resistance through modulation of insulin signals to reverse the responsiveness of insulin. This provides a new target in the treatment of insulin resistance.

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Plasma Glucose–Lowering Effect of Tramadol in Streptozotocin-Induced Diabetic Rats

Cited by 108 publications

References 32 publications

Resistance to Diet-Induced Obesity in μ-Opioid Receptor–Deficient Mice

Resistance to Diet-Induced Obesity in μ-Opioid Receptor–Deficient Mice

Mediation of β-Endorphin by Isoferulic Acid to Lower Plasma Glucose in Streptozotocin-Induced Diabetic Rats

Activation of opioid μ-receptors by loperamide to improve interleukin-6-induced inhibition of insulin signals in myoblast C2C12 cells

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