Abstract
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 GABAB receptor agonist; 1–10 μg/5 μl) or bicuculline (a GABAA 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 GABAA receptor agonist; 1–5 μg/5 μl) or phaclofen (a GABAB 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 GABAB 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 GABAA receptors located in the spinal cord appears to be responsible for tonic up-regulation of the blood glucose level.
Similar content being viewed by others
References
Davidoff RA (1985) Antispasticity drugs: mechanisms of action. Ann Neurol 17(2):107–116
Krantis A (2000) GABA in the mammalian enteric nervous system. News Physiol Sci 15:284–290
Pinard A, Seddik R, Bettler B (2010) GABAB receptors: physiological functions and mechanisms of diversity. Adv Pharmacol 58:231–255
Whiting PJ (2003) GABA-A receptor subtypes in the brain: a paradigm for CNS drug discovery? Drug Discov Today 8(10):445–450
Feldman RG, Kelly-Hayes M, Conomy JP, Foley JM (1978) Baclofen for spasticity in multiple sclerosis. Double-blind crossover and 3-year study. Neurology 28(11):1094–1098
Lazorthes Y, Sallerin-Caute B, Verdie JC, Bastide R, Carillo JP (1990) Chronic intrathecal baclofen administration for control of severe spasticity. J Neurosurg 72(3):393–402
Kawai Unger RH (1983) Effects of gamma-aminobutyric acid on insulin, glucagon, and somatostatin release from isolated perfused dog pancreas. Endocrinology 113(1):111–113
Gilon P, Bertrand G, Loubatières-Mariani MM, Remacle C, Henquin JC (1991) The influence of gamma-aminobutyric acid on hormone release by the mouse and rat endocrine pancreas. Endocrinology 129(5):2521–2529
Bonaventura MM, Catalano PN, Chamson-Reig A, Arany E, Hill D, Bettler B, Saravia F, Libertun C, Lux-Lantos VA (2008) GABAB receptors and glucose homeostasis: evaluation in GABAB receptor knockout mice. Am J Physiol Endocrinol Metab 294(1):E157–E167
Rorsman P, Berggren PO, Bokvist K, Ericson H, Möhler H, Ostenson CG, Smith PA (1989) Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels. Nature 341(6239):233–236
Nonogaki K, Iguchi A, Sakamoto N (1994) Bicuculline methiodide influences the central nervous system to produce hyperglycemia in rats. J Neuroendocrinol 6(4):443–446
Lam TK, Gutierrez-Juarez R, Pocai A, Rossetti L (2005) Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309:943–947
Obici S, Zhang BB, Karkanias G, Rossetti L (2002) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8:1376–1382
Fukushima M, Tokunaga K, Lupien J, Kemnitz JW, Bray GA (1987) Dynamic and static phases of obesity following lesions in PVN and VMH. Am J Physiol 253:R523–R529
Berthoud HR, Jeanrenaud B (1979) Acute hyperinsulinemia and its reversal by vagotomy after lesions of the ventromedial hypothalamus in anesthetized rats. Endocrinology 105:146–151
Minokoshi Y, Okano Y, Shimazu T (1994) Regulatory mechanism of the ventromedial hypothalamus in enhancing glucose uptake in skeletal muscle. Brain Res 649:343–347
Chan O, Zhu W, Ding Y, McCrimmon RJ, Sherwin RS (2006) Blockade of GABA (A) receptors in the ventromedial hypothalamus further stimulates glucagon and sympathoadrenal but not the hypothalamo-pituitary-adrenal response to hypoglycemia. Diabetes 55(4):1080–1087
Antony S, Kumar TP, Kuruvilla KP, George N, Paulose CS (2010) Decreased GABA receptor binding in the cerebral cortex of insulin induced hypoglycemic and streptozotocin induced diabetic rats. Neurochem Res 35(10):1516–1521
Hylden JL, Wilcox GL (1981) Intrathecal substance P elicits a caudally-directed biting and scratching behavior in mice. Brain Res 217:212–215
Defeudis FV (1981) Central GABA-ergic systems and feeding behavior. Neurochem Int 3(5):273–279
Kalsbeek A, Foppen E, Schalij I, Van Heijningen C, van der Vliet J, Fliers E, Buijs RM (2008) Circadian control of the daily plasma glucose rhythm: an interplay of GABA and glutamate. PLoS ONE 3(9):e3194
Kalsbeek A, La Fleur S, Van Heijningen C, Buijs RM (2004) Suprachiasmatic GABAergic inputs to the paraventricular nucleus control plasma glucose concentrations in the rat via sympathetic innervation of the liver. J Neurosci 24(35):7604–7613
Sherin A, Peeyush KT, Naijil G, Chinthu R, Paulose CS (2010) Hypoglycemia induced behavioural deficit and decreased GABA receptor, CREB expression in the cerebellum of streptozotocin induced diabetic rats. Brain Res Bull 83(6):360–366
Wang XL, Zhang Q, Zhang YZ, Liu YT, Dong R, Wang QJ, Guo YX (2011) Downregulation of GABAB receptors in the spinal cord dorsal horn in diabetic neuropathy. Neurosci Lett 490(2):112–115
Morgado C, Pinto-Ribeiro F, Tavares I (2008) Diabetes affects the expression of GABA and potassium chloride cotransporter in the spinal cord: a study in streptozotocin diabetic rats. Neurosci Lett 438(1):102–106
Cavagnini F, Pinto M, Dubini A, Invitti C, Cappelletti G, Polli EE (1982) Effects of gamma aminobutyric acid (GABA) and muscimol on endocrine pancreatic function in man. Metabolism 31(1):73–77
Ozawa K, Miura H, Tamagawa T, Hiyoshi Y, Nonogaki K, Maeda N, Watanabe G, Sakamoto N, Iguchi A (1993) Intrahypothalamic, but not hippocampal, administration of muscimol suppresses hyperglycemia induced by hippocampal neostigmine in anesthetized rats. Life Sci 53(25):1903–1909
Lemus M, Montero S, Cadenas JL, Lara JJ, Tejeda-Chávez HR, Alvarez-Buylla R, de Alvarez-Buylla ER (2008) GabaB receptors activation in the NTS blocks the glycemic responses induced by carotid body receptor stimulation. Auton Neurosci 141(1–2):73–82
Ulrich D, Bettler B (2007) GABA(B) receptors: synaptic functions and mechanisms of diversity. Curr Opin Neurobiol 17(3):298–303
Ortega A (2003) A new role for GABA: inhibition of tumor cell migration. Trends Pharmacol Sci 24(4):151–154
Harrington MA, Oksenberg D, Peroutka SJ (1988) 5-Hydroxytryptamine1A receptors are linked to a Gi-adenylate cyclase complex in rat hippocampus. Eur J Pharmacol 154(1):95–98
García Hermida O, Fontela T, Ghiglione M, Uttenthal LO (1991) Effect of pertussis pretreatment on plasma glucose and insulin responses to lithium in rats. Br J Pharmacol 103(2):1309–1312
Toyota T, Kai Y, Kakizaki M, Sakai A, Goto Y, Yajima M, Ui M (1980) Effects of islet-activating protein (IAP) on blood glucose and plasma insulin in healthy volunteers (phase 1 studies). Tohoku J Exp Med 130(2):105–116
Komatsu M, McDermott AM, Gillison SL, Sharp GW (1995) Time course of action of pertussis toxin to block the inhibition of stimulated insulin release by norepinephrine. Endocrinology 136(5):1857–1863
Sim YB, Park SH, Kang YJ, Jung JS, Ryu OH, Choi MG, Suh HW (2012) Interleukin-1β (IL-1β) increases pain behavior and the blood glucose level: possible involvement of sympathetic nervous system. Pharmacol Biochem Behav 102(1):170–176
Sim YB, Park SH, Kang YJ, Jung JS, Ryu OH, Choi MG, Suh HW (2012) Various pain stimulations cause an increase of the blood glucose level. Animal Cells Syst 16(5):385–390
Sim YB, Park SH, Kang YJ, Kim SS, Kim CH, Kim SJ, Jung JS, Ryu OH, Choi MG, Suh HW (2012) Central anti-diabetic action of biguanide and thizolidinediones in d-glucose fed and streptozotocin-treated mouse models. Neurosci Lett 528(1):73–77
Acknowledgments
This research was supported by Priority Research Centers (2012-R1A6A1048184) and Basic Science Research (2012-0001569) Programs through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology and Hallym University Research Fund, 2012 (HRF-S-2012-5).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sim, YB., Park, SH., Kang, YJ. et al. Effect of GABA Receptor Agonists or Antagonists Injected Spinally on the Blood Glucose Level in Mice. Neurochem Res 38, 1055–1062 (2013). https://doi.org/10.1007/s11064-013-1016-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-013-1016-1