Abstract
γ-Aminobutyric acid (GABA) is considered one of the most important inhibitory transmitter in the central nervous system (CNS). It is assumed that there are at least two types of GABA receptors: GABAA and GABAB. At the level of the CNS, stimulation of the GABAA receptors decreases parasympathic airway constrictor tone while stimulation of GABAB receptors may exert an inhibitory effect on cough. However, most of the GABA effect on lung functions appear mediated through activation of lung GABAB receptors. Stimulation of these peripheral receptors results in the inhibition of the release of acetylcholine from cholinergic nerves as well as of the release of neuropeptides from the C-fibres of the non-adrenergic non-cholinergic (NANC) systems. These effects suggest that GABAB receptor agonists may usefully inhibit bronchoconstriction, microvascular leakage, mucous secretion and inflammatory effects mediated by these neuromediators of the autonomie nervous system. In addition, GABA inhibits the release of anaphylactic mediators. This latter effect requires the integrity of the epithelium and is blocked by inhibition of the cyclooxygenase. Activation of lung GABAB receptors may also account for the antitussive effect of GABA.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Study RE, Barker JL. Diazepam and (—)pentobarbital: fluctuation analysis reveals different mechanisms for potentiation of γ-aminobutyric acid responses in cultured central neurons. Proc Natl Acad Sci 1981; 78: 7180–7184.
Segal M, Barker JL. “Rat hippocampal neurons in culture: properties of GABA-activated Cl” ion conductance. J Neurophysiol 1984; 51: 500–515.
Sieghart W. Multiplicity of GABAA-benzodiazepine receptors. Trends Pharmacol Sci 1989; 10: 407–411.
Sieghart W. GABAA receptors: ligand gated Cl- ion channels modulated by multiple-drug binding sites. Trends Pharmacol Sci 1992; 13: 446–450.
Herb A, Wisden W, Lüddens H, Puia G, Vicini S, Seeburg PH. The third γ-subunit of the γ-aminobutyric acid type A receptor family. Proc Natl Acad Sci 1992; 89: 1433–1437.
Doble A, Benavides J, Ferris O, Bertrand P, Menager J, Vaucher N, et al. Dihydropyridine and peripheral type benzodiazepine binding site: subcellular distribution and molecular size determination. Eur J Pharmacol 1985; 119: 153–167.
Lüddens H, Wisden W. Function and pharmacology of multiple GABAA receptor subunits. Trends Pharmacol Sci 1991; 12: 49–51.
De Blas AL, Vitorica J, Friedrich P. Localization of the GABAA receptor in rat brain with a monoclonal antibody to the 57,000 Mr peptide of the GABAA receptor/benzodiazepine receptor/Cl- channel complex. J Neurosci 1988; 8: 602–614.
Bowery NG, Price GW, Hudson AL, Hill DR, Wilkin GP, Turnbull MJ. GABA receptor multiplicity: Visualization of different receptor types in the mammalian CNS. Neuropharmacology 1984; 23(2B): 219–231.
Bowery N. GABAB receptors and their significance in mammalian pharmacology. Trends Pharmacol Sci 1989; 10: 401–411.
Allen TGJ, Burnstock G. GABAA receptor-mediated increase in membrane chloride conductance in rat paratracheal neurones. Br J Pharmacol 1990; 100: 261–268.
Shirakawa J, Taniyama K, Tanaka C. γ-Aminobutyric acid-induced modulation of acetylcholine release from the guinea-pig lung. J Pharmacol Exp Ther 1987; 243: 364–369.
Tamaoki J, Graf PD, Nadal JA. Effect of γ-aminobutyric acid on neurally mediated contraction of guinea-pig trachealis smooth muscle. J Pharmacol Exp Ther 1987; 243: 86–90.
Chapman RW, Danko G, Rizzo C, Egan RW, Mauser PJ, Kreutner W. Prejunctional GABA-B inhibition of cholinergic, neurally-mediated airway contractions in guinea-pigs. Pulm Pharmacol 1991; 4: 218–224.
Haxhiu MA. Deal EC, Norcia MP, Van Lunteren E, Mitra J, Cherniack NS. Medullary effects of nicotine and GABA on tracheal smooth muscle tone. Respir Physiol 1986; 64: 351–363.
Dolphin AC, Scott RH. Calcium channel currents and their inhibition by (—)-baclofen rat sensory neurons: modulation by guanine nucleotides. J Physiol 1987; 386: 1–17.
Ray NJ, Jones AJ, Keen P. GABAB receptor modulation of the release of substance P from capsaicin-sensitive neurones in the rat trachea in vitro. Br J Pharmacol 1991; 102: 801–804.
Desarmenien M, Feltz P, Occhpinti G, Santangelo F, Schlichter R. Coexistence of GABAA and GABAB receptors on Aδ and C primary afferents. Br J Pharmacol 1984; 81: 327–333.
Belvisi MG, Ichinose M, Barnes PJ. Modulation of non-cholinergic neural bronchoconstriction in guinea-pig airways via GABAB-receptors. Br J Pharmacol 1989; 97: 1225–1231.
Chapman RW, Hey JA, Rizzo CA, Boiser DC. GABAB receptors in the lung. Trends Pharmacol Sci 1993; 14: 26–28.
Barnes PH, Barnaniuk JN, Belvisi MG. Neuropeptides in the respiratory tract. Am Rev Respir Dis 191; 144: 1391-1399.
Boiser DC, Aziz SM, DeGennaro FC, Kreutner W, Egan RW, Siegel MI, Chapman RW. Antitussive effects of GABAB agonists in the cat and guinea-pig. Br J Pharmacol 1993; 110: 491–495.
Doble A, Martin IL. Multiple benzodiazepine receptors: No reason for anxiety. Trends Pharmacol Sci 1992; 13: 76–81.
Langer SZ, Arbilla S. Limitations of the benzodiazepine receptor nomenclature: A proposal for a pharmacological classification as omega receptor subtypes. Fund Clin Pharmacol 1988; 2: 159–170.
Parola AL, Uamamura HI, Larid II HE. Peripheral-type benzodiazepine receptors. Life Sci 1993; 52: 1329–1342.
Gavish M, Katz Y, Bar-Ami S, Weizman R. Biochemical, physiological and pathological aspects of the peripheral benzodiazepine receptor. J Neurochem 1992; 58: 1589–1601.
Verma A, Nye JS, Snyder SH. Porphyrins are endogenous ligands for the mitochondrial (peripheral-type) benzodiazepine receptor. Proc Natl Acad Sci 1987; 84: 2256–2260.
Verma A, Snyder SH. Peripheral type benzodiazepine receptors. Annu Rev Pharmacol Toxicol 1989; 20: 307–322.
Anholt RRH, Pederson PL, De Souza EB, Snyder SH. The peripheral-type benzodiazepine receptor: Localization to the mitochondrial outer membrane. J Biol Chem 1986; 261: 576–583.
Olson JM, Ciliax BJ, Mancini WR, Young AB. Presence of peripheral-type benzodiazepine binding sites on human erythrocyte membranes. Eur J Pharmacol 1988; 152: 47–53.
Berkovich A, Ferrarese C, Calvetti G, Alho H, Marzorati G, Bianchi G, et al. Topology of two DBI receptors in human lymphocytes. Life Sci 1993; 52: 1265–1277.
Oke BO, Suarez-Quian CA, Riond H, Ferrara P, Papadopoulos V. Cell surface localization of the peripheral-type benzodiazepine receptor (PBR) in adrenal cortex. Mol Cell Endocrinol 1992; 87: 1–6.
McEnergy MW, Snowman AM, Trifiletti RR, Synder S. Isolation of the mitochondrial benzodiazepine receptor: Association with the voltage-dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci 1992; 89: 3170–3174.
Mak JC, Barnes PJ. Peripheral type benzodiazepine receptors in human and guinea-pig lung: characterization and autoradiographic distribution. J Pharmacol Exp Ther 1990; 252: 880–885.
Raeburn D, Miller LG, Summer WR. Peripheral type benzodiazepine receptor and airway smooth muscle relaxation. J Pharmacol Exp Ther 1988; 245: 557–562.
Rampe D, Triggle DJ. Benzodiazepines and calcium channel function. Trends Pharmacol Sci 1986; 7: 461–464.
Cantor EH, Kenessey A, Semenuk G, Spector S. Interaction of calcium channel blockers with non-neuronal benzodiazepine binding sites. Proc Natl Acad Sci 1984; 81: 1549–1552.
Thuillez C, Loueslati H, Duhaze P, Giudicelli J. Functional antagonism between PK11195, a peripheral benzodiazepine receptor antagonist, and nicardipine at the vascular level in healthy subjects: A peripheral hemodynamic study. J Cardiovasc Pharmacol 1989; 13: 307–313.
Wu PH, Phillis JW, Bender SA. Do benzodiazepines bind at adenosine sites in the CNS? Life Sci 1981; 28: 1023–1031.
Phillis JW, O’Regan MH. Benzodiazepine interaction with adenosine systems explains some anomalies in GABA hypothesis. Trends Pharmacol Sci 1988; 9: 153–154.
Advenier C, Devillier P, Blanc M, Gnassounou JP. Peripheral type benzodiazepine receptors and response to adenosine on the guinea-pig isolated trachea. Pulm Pharmacol 1990; 3: 137–144.
Candenas ML, Devillier P, Naline E, Advenier C. Influence of diazepam, alpidem, zolpidem and zopiclone on the response to adenosine of the guinea-pig isolated trachea. Fund Clin Pharmacol 1991; 5: 1–10.
Devillier P, Candenas ML, Naline E, Advenier C. Influence of benzodiazepines on the response of the guinea-pig trachea to the contractile action of adenosine. J Pharmacol 1992; 214: 67–74.
Escubedo E, Camarasa J, Pallas M, Adzet T. Peripheral benzodiazepines potentiate the effect of adenosine in rat vas deferens. J Pharm Pharmacol 1991; 43: 49–50.
Hammond JR, Jarvis SM, Paterson AR, Clanachan AS. Benzodiazepine inhibition of nucleoside transport in human erythrocytes. Biochem Pharmacol 1983; 32: 1229–1234.
Marano G, Massotti M, Spagnolo A, Carpi A. Enhancement of pharmacologically induced bronchoconstriction by Ro5-4864. Eur J Pharmacol 1990; 179: 237–240.
Haxhiu MA, Van Lunteren E, Cherniack NS, Deal EC. Benzodiazepines acting on ventral surface of medulla cause airway dilation. Am J Physiol 1989; 257: R810–R815.
Fonlupt P, Croset M, Lagarde M. Benzodiazepine analogues inhibit arachidonate-induced aggregation and thromboxane synthesis in human platelets. Br J Pharmacol 1990; 101: 920–924.
Papadopoulus V, Muklin AG, Costa E, Krueger KE. The peripheral-type benzodiazepine receptor is functionally linked to leydig cell steroidogenesis. J Biol chem 1990; 265: 3772–3779.
Garnier M, Dimchev AB, Boujrad N, Price JM, Musto NA, Papadopoulos V. In vitro reconstitution of a functional peripheral-type benzodiazepine receptor from mouse leydig tumor cells. Mol Pharmacol 1994; 45: 201–211.
Taupin V, Herbelin A, Descamps-Latscha B, Zavala F. Endogenous anxiogenic peptide, ODN-binding inhibitor, and benzodiazepines enhance the production of interleukin-1 and tumor necrosis factor by human monocytes. Lymphokine Cytokine Res 1991; 1: 7–13.
Taupin V, Gogusev J, Descamps-Latscha B, Zavala F. Modulation of tumor necrosis factor-α, interleukin-1β, interleukin 6, interleukin 8 and granulocyte/macrophage colony-stimulating factor expression in human monocytes by an endogenous anxiogenic benzodiazepine ligand, triakontetraneuropeptide: evidence for a role of prostaglandins. Mol Pharmacol 1993; 43: 64–69.
Watson ML, Smith D, Bourne AD, Thompson RC, Westwick J. Cytokines contribute to airway dysfunction in antigen-challenged guinea-pigs: Inhibition of airway hyperreactivity, pulmonary eosinophil accumulation, and tumor necrosis factor generation by pre-treatment with an interleukin-1 receptor antagonist. Am J Respir Cell Mol Biol 1993; 8: 365–369.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1995 Birkhäuser Verlag Basel/Switzerland
About this chapter
Cite this chapter
Devillier, P., Bessard, G., Advenier, C. (1995). GABA and Benzodiazepines. In: Raeburn, D., Giembycz, M.A. (eds) Airways Smooth Muscle: Neurotransmitters, Amines, Lipid Mediators and Signal Transduction. Respiratory Pharmacology and Pharmacotherapy. Birkhäuser Basel. https://doi.org/10.1007/978-3-0348-7504-2_9
Download citation
DOI: https://doi.org/10.1007/978-3-0348-7504-2_9
Publisher Name: Birkhäuser Basel
Print ISBN: 978-3-0348-7506-6
Online ISBN: 978-3-0348-7504-2
eBook Packages: Springer Book Archive