Abstract
Baclofen (β-chlorophenyl GABA) is a stereospecific agonist at GABA type B (GABAB) receptors and is inactive at GABAA receptors. It has therefore been employed as a marker for GABAB sites. Its selectivity for this receptor provides a unique pharmacology which is covered in this chapter. Numerous effects have been reported but currently only its anti-spasticity and analgesic actions are utilized in clinical medicine. It is the preferred treatment in spasticity of different origins. Its potential for use in other conditions, for example, in reducing drug addiction, in the treatment of gastroesophageal reflux disease, chronic cough and hiccup is very strong. However, as it is a directly acting receptor agonist its action is likely to be diminished by desensitization. Moreover, its access to the CNS is limited requiring the administration of high doses. This increases the chance of unwanted side effects. To overcome this in spasticity, the administration of lower doses into the intrathecal space through an indwelling cannula has had a major influence on the acceptance of the drug by patients. In other conditions, an alternative approach is required and the possible solution may be the use of positive allosteric modulators of the GABAB receptor. This could reduce receptor desensitization and improve access to the site of action.
Keywords
- Baclofen
- Spasticity
- Analgesia
- Epilepsies
- Antidepressant
- Cognition
- Addiction
- Hiccup
- Cough
- Gastroesophageal reflux disease
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Adams, C. L., & Lawrence, A. J. (2007). CGP7930: A positive allosteric modulator of the GABAB receptor. CNS Drug Reviews, 13, 308–316.
Addolorato, G., Caputo, F., Capristo, E., Colombo, G., Gessa, G. L., & Gasbarrini, G. (2000). Ability of baclofen in reducing alcohol craving and intake: II—Preliminary clinical evidence. Alcoholism, Clinical and Experimental Research, 24, 67–71.
Addolorato, G., Caputo, F., Capristo, E., Domenicali, M., Bernardi, M., Janiri, L., et al. (2002). Baclofen efficacy in reducing alcohol craving and intake: A preliminary double-blind randomized controlled study. Alcohol and Alcoholism, 37, 504–508.
Agabio, R., & Colombo, G. (2014). GABAB receptor ligands for the treatment of alcohol use disorder: Preclinical and clinical evidence. Frontiers in Neuroscience, 8, 140.
Agabio, R., & Colombo, G. (2015). GABAB receptor as therapeutic target for drug addiction: From baclofen to allosteric modulators. Psychiatria Polska, 49, 215–223.
Akhondzadeh, S., Ahmadi-Abhari, S. A., Assadi, S. M., Shabestari, O. L., Kashani, A. R., & Farzanehgan, Z. M. (2000). Double-blind randomized controlled trial of baclofen vs clonidine in the treatment of opiates withdrawal. Journal of Clinical Pharmacy and Therapeutics, 25, 347–353.
Aley, K. O., & Kulkarni, S. K. (1991). Baclofen analgesia in mice: A GABAB-mediated response. Methods and Findings in Experimental and Clinical Pharmacology, 13, 681–686.
Al-Kadalry, A. T., Wicky, G., Nicolo, D., & Vuadens, P. (2015). Influence of intrathecal baclofen on the level of consciousness and mental functions after extremely severe traumatic brain injury: Brief report. Brain Injury, 29, 527–532.
Arai, S., Takuma, K., Mizoguchi, H., Ibi, D., Nagai, T., Kamei, H., et al. (2009). GABAB receptor agonist baclofen improves methamphetamine-induced cognitive deficit in mice. European Journal of Pharmacology, 602, 101–104.
Barral, J., Toro, S., Galarraga, E., & Bargas, J. (2000). GABAergic presynaptic inhibition of rat neostriatal afferents is mediated by Q-type Ca2+ channels. Neuroscience Letters, 283, 33–36.
Baumann, A., Weicker, T., Alb, I., & Audibert, G. (2014). Baclofen for the treatment of hiccup related to brainstem compression. Annales Françaises d’Anesthèsie et de Rèanimation, 33, 27–28.
Becker, R., Alberti, O., & Bauer, B. L. (1997). Continuous intrathecal baclofen infusion in severe spasticity after traumatic or hypoxic brain injury. Journal of Neurology, 244, 160–166.
Bein, H. J. (1972). Pharmacological differentiation of muscle relaxants. In W. Birkmayer (Ed.), Spasticity—A topical survey (pp. 76–82). Vienna: Huber.
Birkmayer, W., Danielczyk, W., & Weller, G. (1967). On the objectivization of the myotonolitic effect of an aminobutyric acid derivative (Ciba 34647-Ba). Wiener Medizinische Wochenschrift (1946), 117, 7–9.
Boeckxstaens, G., Denison, H., Ruth, M., Adler, J., Silberg, D., & Sifrim, D. (2009). Effect of AZD3355, a novel GABAB agonist, on reflux and lower esophageal sphincter function in patients with GERD with symptoms despite proton pump inhibitor treatment. Gastroenterology, 136(Suppl. 1), M1861.
Bonouvrie, L., Becher, J., Soudant, D., Buizer, A., van Ouwerkerk, W., Vles, G., et al. (2016). The effect of intrathecal baclofen treatment on activities of daily life in children and young adults with cerebral palsy and progressive neurological disorders. European Journal of Paediatric Neurology, 20(4), 538–544. doi:10.1016/ejpn.2016.02.013.
Bortolato, M., Frau, R., Orrù, M., Fà, M., Dessì, C., Puligheddu, M., et al. (2010). GABAB receptor activation exacerbates spontaneous spike-and-wave discharges in DBA/2J mice. Seizure, 19, 226–231.
Bowery, N. G., Price, G. P., & Hudson, A. L. (1987). GABAA and GABAB receptor site distribution in rat central nervous system. Neuroscience, 20, 365–385.
Brar, S. P., Smith, M. B., Nelson, I. M., Franklin, G. M., & Cobble, N. D. (1991). Evaluation of treatment protocols on minimal to moderate spasticity in multiple sclerosis. Archives of Physical Medicine and Rehabilitation, 72, 186–189.
Brogden, R. N., Speight, T. M., & Avery, G. S. (1974). Baclofen: A preliminary report of its pharmacological properties and therapeutic efficacy in spasticity. Drugs, 8, 1–14.
Brown, J. W., Moeller, A., Schmidt, M., Turner, S. C., Nimmrich, V., Ma, J., et al. (2016). Anticonvulsant effects of structurally diverse GABAB positive allosteric modulators in the DBA/2J audiogenic seizure test: Comparison to baclofen and utility as a pharmacodynamics screening model. Neuropharmacology, 101, 358–369.
Brusberg, M., Ravenefjord, A., Martinsson, R., Larsson, H., Martinez, V., & Lindström, E. (2009). The GABA(B) receptor agonist, baclofen, and the positive allosteric modulator, CGP7930, inhibit visceral pain-related responses to colorectal distension in rats. Neuropharmacology, 56, 362–367.
Buonaguro, V., Scelsa, B., Curci, D., Monforte, S., Iuorno, T., & Motta, F. (2005). Epilepsy and intrathecal baclofen therapy in children with cerebral palsy. Pediatric Neurology, 33, 110–113.
Cange, L., Johnston, E., Rydholm, H., Lehmann, A., Finizia, C., Lundell, L., et al. (2002). Baclofen-mediated gastro-oesophageal acid reflux control in patients with established reflux disease. Alimentary Pharmacology and Therapeutics, 16, 869–873.
Carletti, R., Libri, V., & Bowery, N. G. (1993). The GABABantagonist CGP36742 enhances spatial learning performance and antagonizes baclofen-induced amnesia in mice. British Journal of Clinical Pharmacology, 109, 74.
Castro-Lopes, J. M., Tavares, I., Tölle, T. R., Coito, A., & Coimbra, A. (1992). Increase in GABAergic cells and GABA levels in the spinal cord in unilateral inflammation of the hindpaw of the rat. European Journal of Neuroscience, 4, 296–301.
Chaignot, C., Weill, A., Ricordeau, P., & Alla, F. (2015). Use in France of baclofen for alcohol dependence from 2007 to 2013: Cohort study based on the databases SNTTRAM and PMSTL. Thérapie, 70, 443–453.
Chapman, R. W., Hey, J. A., Rizzo, C. A., & Bolser, D. C. (1993). GABAB receptors in the lung. Trends in Pharmacological Sciences, 14, 26–29.
Chu, D. C. M., Albin, R. L., Young, A. B., & Penney, J. B. (1990). Distribution and kinetics of GABAB binding sites in rat central nervous system: A quantitative autoradiography study. Neuroscience, 34, 341–357.
Chung, K. F. (2015). NMDA and GABA receptors as potential targets in cough hypersensitivity syndrome. Current Opinion in Pharmacology, 22, 29–36.
Colombo, G., Addolorato, G., Agabio, R., Carai, M. A. M., Pibiri, F., Serra, S., et al. (2004). Role of GABAB receptor in alcohol dependence: Reducing effect of baclofen on alcohol intake and alcohol motivational properties in rats and amelioration of alcohol withdrawal syndrome and alcohol craving in human alcoholics. Neurotoxicity Research, 6, 403–414.
Corrigall, W. A., Coen, K. M., Adamson, K. L., Chow, B. L., & Zhang, J. (2000). Response of nicotine self-administration in the rat to manipulations of mu-opioid and gamma-aminobutyric acid receptors in the ventral tegmental area. Psychopharmacology, 149, 107–114.
Cortez, M. A., McKerlie, C., & Snead, O. C. (2001). A model of atypical absence seizures: EEG, pharmacology, and developmental characterization. Neurology, 56, 341–349.
Cousins, M. S., Roberts, D. C., & de Wit, H. (2002). GABAB receptor agonists for the treatment of drug addiction: A review of recent findings. Drug and Alcohol Dependence, 65, 209–220.
Cross, J. A., & Horton, R. W. (1987). Are increases in GABAB receptors consistent findings following chronic antidepressant administration? European Journal of Pharmacology, 141, 159–162.
Cross, J. A., & Horton, R. W. (1988). Effects of chronic oral administration of the antidepressants desmethylimipramine and zimelidine on rat cortical GABAB binding sites: A comparison with 5HT2 binding site changes. British Journal of Clinical Pharmacology, 93, 331–336.
Cuny, H., de Faoite, A., Huynh, T. G., Yasuda, T., Berecki, G., & Adams, D. J. (2012). γ-Aminobutyric acid type B (GABAB) receptor expression is needed for inhibition of N-type (Cav2.2) calcium channels by analgesic α-conotoxins. Journal of Biological Chemistry, 287, 23948–23957.
Curtis, D. R., Game, C. J. A., Johnston, G. A. R., & McCulloch, R. M. (1974). Central effects of β-(p-chlorophenyl)-γ-aminobutyric acid. Brain Research, 70, 493–499.
Curtis, D. R., & Watkins, J. C. (1965). The pharmacology of amino acids related to gamma-aminobutyric acid. Pharmacological Reviews, 17, 347–391.
Cutting, D. A., & Jordan, C. C. (1975). Alternative approaches to analgesia: Baclofen as a model compound. British Journal of Clinical Pharmacology, 54, 171–179.
Davies, J., & Watkins, J. C. (1974). The action of β-phenyl-GABA derivatives on neurons of the cat cerebral cortex. Brain Research, 70, 501–505.
De Sousa, N. J., Beninger, R., Jhamandas, K., & Boegman, R. J. (1994). Stimulation of GABAB receptors in the basal forebrain selectivity impairs working memory of rats in the double Y-maze. Brain Research, 641, 29–38.
Demaziere, J., Saissy, J. M., Vitris, M., Seck, M., Marcoux, L., & Ndiaye, M. (1991). Intermittent intrathecal baclofen for severe tetanus. Lancet, 337(8738), 427.
Dent, J., El-Serag, H. B., Wallander, M. A., & Johansson, S. (2005). Epidemiology of gastroesophageal reflux disease: A systemic review. Gut, 54, 710–717.
Dicpinigaitis, P. V., & Dobkin, J. B. (1997). Antitussive effect of the GABA-agonist baclofen. Chest, 111, 996–999.
Dicpinigaitis, P. V., & Rauf, K. (1998). Treatment of chronic refractory cough with baclofen. Respiration, 65, 86–88.
Doze, V. A., Cohen, G. A., & Madison, D. V. (1995). Calcium channel involvement in GABAB receptor-mediated inhibition of GABA release in area CA1 of the rat hippocampus. Journal of Neurophysiology, 74, 43–53.
Dunlap, K. (1981). Two types of γ-aminobutyric acid receptor on embryonic sensory neurons. British Journal of Pharmacology, 74, 579–585.
Dutar, P., & Nicoll, R. A. (1988). A physiological role for GABAB receptors in the central nervous system. Nature, 332, 156–158.
Engrand, N., Guerot, E., Rouamba, A., & Vilain, G. (1999). The efficacy of intrathecal baclofen in severe tetanus. Anesthesiology, 90, 1773–1776.
Erdo, S. L., & Bowery, N. G. (Eds.). (1986). GABAergic mechanisms in mammalian periphery (pp. 1–364). New York: Raven.
Franklin, T. R., Harper, D., Kampman, K., Kildea-McCrea, S., Jens, W., Lynch, K. G., et al. (2009). The GABAB agonist baclofen reduces cigarette consumption in a preliminary double-blind placebo-controlled smoking reduction study. Drug and Alcohol Dependence, 103, 30–36.
Froestl, W., Gallagher, M., Jenkins, H., Madrid, A., Melcher, T., Teichman, S., et al. (2004). SGS742: The first GABABreceptor antagonist in clinical trials. Biochemical Pharmacology, 68, 1479–1487.
Fromm, G. H., & Terrence, C. F. (1987). Comparison of L-baclofen and racemic baclofen in trigeminal neuralgia. Neurology, 37, 1725–1728.
Fromm, G. H., Terrence, C. F., Chatta, A. S., et al. (1980). Baclofen in trigeminal neuralgia: Its effect on the spinal trigeminal nucleus: A pilot study. Archives of Neurology, 15, 240–244.
Fromm, G. H., Terrence, C. F., Chatta, A. S., & Glass, J. D. (1984). Baclofen in the treatment of trigeminal neuralgia: Double-blind study and long-term follow-up. Annals of Neurology, 15, 240–244.
Gale, K. (1992). GABA and epilepsy: Basic concepts from preclinical research. Epilepsia, 33(Suppl. 5), S3–S12.
Gamardella, A., Manna, I., Labate, A., Chifari, R., La Russa, A., Serra, P., et al. (2003). GABA(B) receptor 1 polymorphism (G1465A) is associated with temporal lobe epilepsy. Neurology, 60, 560–563.
Genkova-Papazova, M. G., Perkova, B., Shishkova, N., & Lazarova-Bakarova, M. (2000). The GABAB antagonist CGP36742 prevents PTZ-kindling-provoked amnesia in rats. European Neuropsychopharmacology, 10, 273–278.
Getova, D. P., & Bowery, N. G. (1998). The modulatory effects of high affinity GABAB receptor antagonists in an active avoidance learning paradigm in rats. Psychopharmacology, 137, 369–373.
Getova, D. P., & Dimitrova, D. D. (2007). Effects of GABAB receptor antagonists CGP63360, CGP76290A and CGP76291A on learning and memory processes in rodents. Central European Journal of Medicine, 2, 280–293.
Gianino, J. M., York, M. M., Paice, J. A., & Shott, S. (1998). Quality of life: Effect of reduced spasticity from intrathecal baclofen. Journal of Neuroscience Nursing, 30, 47–54.
Giesser, B. (1985). Multiple sclerosis. Current concepts in management. Drugs, 29, 88–95.
Giotti, A., Bartolini, A., Failli, P., Gentilini, G., Malcangio, M., & Zilletti, L. (1990). Review of peripheral GABAB effects. In N. G. Bowery, H. Bittiger, & H.-R. Olpe (Eds.), GABAB receptors in mammalian function (pp. 101–123). Chichester: Wiley.
Grimm, D. R., DeLuca, R. V., Lesser, M., Bauman, W. A., & Almenoff, P. L. (1997). Effects of GABAB agonist baclofen on bronchial hyperreactivity to inhaled histamine in subjects with cervical spinal cord injury. Lung, 175, 333–341.
Guelaud, C., Similowski, T., Bizec, J., Cabane, J., Whitelaw, W. A., & Derenne, J. P. (1995). Baclofen therapy for chronic hiccup. European Respiratory Journal, 8, 235–237.
Haney, M., Hart, C. L., & Foltin, R. W. (2006). Effects of baclofen on cocaine self-administration: Opioid- and nonopioid-dependent volunteers. Neuropsychopharmacology, 31, 1814–1821.
Harrison, N. L., Lambert, N. A., & Lovinger, D. M. (1990). Presynaptic GABAB receptors on rat hippocampal neurons. In N. G. Bowery, H. Bittiger, & H.-R. Olpe (Eds.), GABAB receptors in mammalian function (pp. 208–221). Chichester: Wiley.
Heetla, H. W., Proost, J. H., Molmans, B. H., Staal, M. J., & van Laar, T. (2016). A pharmacokinetic-pharmacodynamic model for intrathecal baclofen in patients with severe spasticity. British Journal of Clinical Pharmacology, 81, 101–112.
Hering-Hanit, R. (1999). Baclofen for the prevention of migraine. Cephalalgia, 19, 589–591.
Hering-Hanit, R., & Gadoth, N. (2000). Baclofen in cluster headache. Headache, 40, 48–51.
Hill, D. R. (1985). GABAB receptor modulation of adenylate cyclase activity in rat brain slices. British Journal of Clinical Pharmacology, 84, 249–257.
Hill, D. R., & Bowery, N. G. (1981). 3H-Baclofen and 3H-GABA bind to bicuculline insensitive GABAB sites in rat brain. Nature, 290, 149–152.
Hudgson, P., & Weightman, D. (1971). Baclofen in the treatment of spasticity. British Medical Journal, 15, 7.
Huynh, T. G., Cuny, H., Siesinger, P. A., & Adams, D. J. (2015). Novel mechanism of voltage-gated N-type (Cav2.2) calcium channel inhibition revealed through α-conotoxin Vc1.1 activation of the GABA(B) receptor. Molecular Pharmaceutics, 87, 240–250.
Imbert, B., Alvarez, J. C., & Simon, N. (2015). Anticraving effect of baclofen in alcohol-dependent patients. Alcoholism, Clinical and Experimental Research, 39, 1602–1608.
Inaba, Y., D’Antuono, M., Bertazzoni, G., Biagini, G., & Avoli, M. (2009). Diminished presynaptic GABA(B) receptor function in the neocortex of a genetic model of absence epilepsy. Neurosignals, 17, 121–131.
Isaacson, J. S. (1998). GABAB receptor-mediated modulation of presynaptic currents and excitatory transmission at a fast central synapse. Journal of Neurophysiology, 80, 1571–1576.
Jones, R. F., Burke, D., Marosszeky, J. E., & Gillies, J. D. (1970). A new agent for the control of spasticity. Journal of Neurology, Neurosurgery & Psychiatry, 33, 464–468.
Kahn, R., Biswas, K., Childress, A. R., Shoptaw, S., Fudala, P. J., Gorgon, L., et al. (2009). Multi-center trial of baclofen for abstinence initiation in severe cocaine-dependent individuals. Drug Alcohol Dependence, 103, 59–64.
Kalinichev, M., Donovan-Rodriguez, T., Girard, F., Riguet, E., Rouillier, M., Bournique, B., et al. (2014). Evaluation of peripheral versus central effects of GABA(B) receptor activation using a novel, positive allosteric modulator of the GABA(B) receptor ADX71943, a pharmacological tool compound with a fully peripheral activity profile. British Journal of Clinical Pharmacology, 171, 4941–4954.
Karbon, E. W., Duman, R. S., & Enna, S. J. (1984). GABAB receptors and norepinephrine-stimulated cAMP production in rat brain cortex. Brain Research, 306, 327–332.
Keberle, H., & Faigle, J. W. (1968). Synthesis and structure-activity relationships of the γ-aminobutyric acid derivatives. In W. Birkmayer (Ed.), Spasticity—A topical survey (pp. 90–93). Vienna: Huber.
Keegan, D. L., Richardson, J. S., & Kirby, A. R. (1983). A possible neurochemical basis for the neuropsychiatric aspects of baclofen therapy. International Journal of Neuroscience, 20, 249–254.
Khurana, S. R., & Gang, D. S. (2014). Spasticity and the use of intrathecal baclofen in patients with spinal cord injury. Physical Medicine and Rehabilitation Clinics of North America, 25, 655–669.
Krach, L. E. (2009). Intrathecal baclofen use in adults with cerebral palsy. Developmental Medicine and Child Neurology, 51(Suppl. 4), 106–112.
Lambert, N. A., & Wilson, W. A. (1996). High-threshold Ca2+ currents in rat hippocampal interneurons and their selective inhibition by activation of GABAB receptors. Journal of Physiology, 492, 115–127.
Lasarge, C. L., Banuelos, C., Mayse, J. D., & Bizon, J. L. (2009). Blockade of GABA(B) receptors completely reverses age-related learning impairment. Neuroscience, 164, 941–947.
Lehmann, A., Antonsson, M., Bremner-Danielson, M., Flärdh, M., Hansson-Brändén, L., & Kärrberg, L. (1999). Activation of the GABAB receptor inhibits transient lower esophageal sphincter relaxations in dogs. Gastroenterology, 117, 1147–1154.
Lehmann, A., Antonsson, M., Holmberg, A., Blackshaw, L. A., Brändén, L., Bräuner-Osborne, H., et al. (2009). (R)-(3-amino-2-fluoropropyl) phosphinic acid (AZD3355), a novel GABAB receptor agonist, inhibits transient lower esophageal sphincter relaxation through a peripheral mode of action. Journal of Pharmacol and Experimental Therapeutics, 331, 504–512.
Leisen, C., Langguth, P., Herbert, B., Dressler, C., Koggel, A., & Spahn-Langguth, H. (2003). Lipophilicities of baclofen ester prodrug correlate with affinities to the ATP-dependent efflux pump P-glycoprotein: Relevance for their permeation across the blood-brain barrier? Pharmaceutical Research, 20, 772–778.
Lesouef, N., Bellet, F., Mourier, G., & Beyens, M. N. (2014). Efficacy of baclofen on abstinence and craving in alcohol-dependent patients: A meta-analysis of randomized controlled trials. Thérapie, 69, 427–435.
Ling, W., Shoptaw, S., & Majewska, D. (1998). Baclofen as a cocaine anti-craving medication: A preliminary clinical study. Neuropsychopharmacology, 18, 403–404.
Liu, Q. Y., Wang, C. Y., Cai, Z. L., Xu, S. T., Liu, W. X., Xiao, P., et al. (2014). Effects of intrahippocampal GABAB receptor antagonist treatment on the behavioral long-term potentiation and Y-maze learning performance. Neurobiology of Learning and Memory, 114, 26–31.
Lloyd, K. G. (1989). GABA and depression. In G. Nistico & N. G. Bowery (Eds.), GABA basic research and clinical applications (pp. 301–343). Pythagora: Rome.
Lloyd, K. G., Thuret, F., & Pilc, A. (1985). Upregulation of γ-aminobutyric acid (GABA)B binding sites in rat frontal cortex: A common action of repeated administration of different classes of antidepressants and electroshock. Journal of Pharmacol and Experimental Therapeutics, 235, 191–199.
Lorrai, I., Maccioni, P., Gessa, G. L., & Colombo, G. (2016). R (+)-Baclofen but not S (−) baclofen alters alcohol self administration in alcohol preferring rats. Frontiers in Psychiatry, 7, 68. doi:10.3389/fpsyt.2016.04.028.
Luo, P., Chen, C., Lu, Y., Fu, T., Lu, Q., Xu, X., et al. (2016). Baclofen ameliorates spatial working memory impairments induced by chronic cerebral hypoperfusion via up-regulation of HCN2 expression in the PPC in rats. Behavioural Brain Research, 308, 6–13.
Luscher, C., Jan, I. Y., Stoffel, M., Malenka, R. C., & Nicoll, R. A. (1997). G-protein inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons. Neuron, 19, 687–695.
Maccioni, P., Vargiolu, D., Thomas, A. W., Malherbe, P., Mugnaini, C., Corelli, F., et al. (2015). Inhibition of alcohol self-administration by positive allosteric modulators of the GABAB receptor in rats: Lack of tolerance and potentiation of baclofen. Psychopharmacology, 232, 1831–1841.
Malcangio, M., & Bowery, N. G. (1993). Gamma-aminobutyric acidB but not gamma-aminobutyric acidA receptor activation inhibits electrically evoked substance P-like immunoreactivity release from rat spinal cord in vitro. Journal of Pharmacol and Experimental Therapeutics, 266, 1490–1496.
Malcangio, M., & Bowery, N. G. (1994). Spinal cord SP release and hyperalgesia in monoarthritic rats: Involvement of the GABAB receptor system. British Journal of Clinical Pharmacology, 113, 1561–1566.
Malcangio, M., & Bowery, N. G. (1996). Calcitonin gene-related peptide content, basal outflow and electrically evoked release from monoarthritic rat spinal cord in vitro. Pain, 66, 351–358.
Manning, J. P., Richards, D. A., & Bowery, N. G. (2003). Pharmacology of absence epilepsy. Trends in Pharmacological Sciences, 17, 457–462.
Mathur, S. N., Chu, S. K., McCormick, Z., Chang Chien, G. C., & Marciniak, C. M. (2014). Long-term intrathecal baclofen: Outcomes after more than 10 years of treatment. PM & R: The Journal of Injury, Function, and Rehabilitation, 6, 506–513.
Meeren, H., van Luitelaar, G., Lopes da Silva, F., & Coenen, A. (2005). Evolving concepts on the pathophysiology of absence seizures. Archives of Neurology, 62, 371–376.
Meldrum, B., & Horton, R. (1980). Effects of the bicyclic GABA agonist, THIP, on myoclonic and seizure responses in mice and baboons with reflex epilepsy. European Journal of Pharmacology, 61, 231–237.
Miner, P. B., Jr., Silberg, D. G., Ruth, M., Miller, F., & Pandolfino, J. (2014). Dose-dependent effects of lesogaberan on reflux measures in patients with refractory gastroesophageal reflux disease: A randomized, placebo-controlled study. BMC Gastroenterol, 14, 188.
Mombereau, C., Kaupmann, K., Froestl, W., Sansig, G., van der Putten, H., & Cryan, J. F. (2004). Genetic and pharmacological evidence of a role for GABAB receptors in the modulation of anxiety- and antidepressant-like behavior. Neuropsychopharmacology, 29, 1050–1062.
Mueller, H., Borner, U., Zierski, J., & Hempelmann, G. (1987). Intrathecal baclofen for treatment of tetanus-induced spasticity. Anesthesiology, 66, 76–79.
Nagakawa, Y., Ishima, T., Ishibashi, Y., Tsuji, M., & Takashima, T. (1996). Involvement of GABAB receptor systems in experimental depression: Baclofen but not bicuculline exacerbates helplessness in rats. Brain Research, 741, 240–245.
Naito, Y. (2014). Intrathecal baclofen therapy and management of severe spasticity. Brain and Nerve, 66, 1049–1055.
Nanninga, J. B., Frost, F., & Penn, R. (1989). Effect of intrathecal baclofen on bladder and sphincter function. Journal of Urology, 142, 101–105.
Navarrete-Opazo, A. A., Gonzalez, W., & Nahuelhual, P. (2016). Effectiveness of oral baclofen in the treatment of spasticity in children and adolescents with cerebral palsy. Archives of Physical Medicine and Rehabilitation, 97, 604–618.
Nicoll, R. A. (2004). My close encounter with GABAB receptors. Biochemical Pharmacology, 68, 1667–1674.
O’Brien, C. F., Seeberger, I. C., & Smith, D. B. (1996). Spasticity after stroke: Epidemiology and optimal treatment. Drugs & Aging, 9, 332–340.
Ochs, G. A. (1993). Intrathecal baclofen. Baillière’s Clinical Neurology, 2, 73–86.
Odagaki, Y., & Koyama, T. (2001). Identification of G alpha subtype(s) involved in gamma-aminobutyric acid (B) receptor-mediated high affinity guanosine triphosphate activity in rat cerebral cortical membranes. Neuroscience Letters, 297, 137–141.
Odagaki, Y., Nishi, N., & Koyama, T. (2000). Functional coupling of GABA(B) receptors with G proteins that are sensitive to N-ethylmaleimide treatment, suramin and benzalkonium chloride in rat cerebral cortical membranes. Journal of Neural Transmission, 107, 1101–1116.
Okazaki, T., Saito, Y., Ueda, R., Sughara, S., Tamasaki, A., Nishimura, Y., Ohno, K., et al. (2016). Effect of intrathecal baclofen on delayed-onset paroxysmal dystonia due to compression injury resulting from congenital and progressive spinal bone deformaties in chondrodysplasia punctata. Pediatric Neurology, 56, 80–85.
Olsen, R. W., Bureau, M., Houser, C. R., Delgado-Escueta, A. V., Richards, J. G., & Möhler, H. (1992). GABA/Benzodiazepine receptors in human focal epilepsy. Epilepsy Research. Supplement, 8, 383–391.
Pacey, L. K., Heximer, S. P., & Hampson, D. R. (2009). Increased GABA(B) receptor-mediated signaling reduces the susceptibility of fragile X knockout mice to audiogenic seizures. Molecular Pharmacology, 76, 18–24.
Pacey, L. K., Tharmlingam, S., & Hampson, D. R. (2011). Subchronic administration and combination metabotropic glutamate and GABAB receptor drug therapy in fragile X syndrome. Journal of Pharmacol and Experimental Therapeutics, 338, 897–905.
Penn, R. D., & Kroin, J. S. (1984). Intrathecal baclofen alleviates spinal cord spasticity. Lancet, 323(8385), 1078.
Penn, R. D., & Kroin, J. S. (1985). Continuous intrathecal baclofen for severe spasticity. Lancet, 326(8447), 125–127.
Pitsikas, N., Rigamonti, A. E., Cella, S. G., & Muller, E. E. (2003). The GABAB receptor and recognition memory: Possible modulation of its behavioral effects by the nitrergic system. Neurosience, 118, 1121–1127.
Porrino, L. J., Hampson, R. E., Opris, I., & Deadwyler, S. A. (2013). Acute cocaine induced deficits in cognitive performance in rhesus macaque monkeys treated with baclofen. Psychopharmacology, 225, 105–114.
Post, R. M., Ketter, T. A., Joffe, R. T., & Kramlinger, K. L. (1991). Lack of beneficial effects of l-baclofen in affective disorder. International Clinical Psychopharmacology, 6, 197–207.
Potes, C. S., Neto, F. L., & Castro-Lopes, J. M. (2006). Administration of baclofen, a gamma-aminobutyric acid type B agonist in the thalamic ventrobasal complex, attenuates allodynia in monoarthritic rats subjected to the ankle-bend test. Journal of Neuroscience Research, 83, 515–523.
Prosser, H. M., Gill, C. H., Hirst, W. D., Grau, E., Robbins, M., Calver, A., et al. (2001). Epileptogenesis and enhanced prepulse inhibition in GABA(B1)-deficient mice. Molecular and Cellular Neurosciences, 17(6), 1059–1070.
Proudfit, H. K., & Levy, R. A. (1978). Delimitation of neuronal substrates necessary for the analgesic actions of baclofen and morphine. European Journal of Pharmacology, 47, 159–166.
Rawlins, P. (1998). Patient management of cerebral origin spasticity with intrathecal baclofen. Journal of Neuroscience Nursing, 30, 32–35, 40–46.
Roberts, D. C. S., & Andrews, M. M. (1997). Baclofen suppression of cocaine self-administration: Demonstration using a discrete trials procedure. Psychopharmacology, 131, 271–277.
Rolland, B., Labreuche, J., Duhammel, A., Deheul, S., Gautier, S., Auffret, M., et al. (2015). Baclofen for alcohol dependence: Relationships between baclofen and alcohol dosing and the occurrence of major sedation. European Neuropsychopharmacology, 25, 1631–1636.
Santos, A. E., Carvalho, C. M., Macedo, T. A., & Carvalho, A. P. (1995). Regulation of intracellular [Ca2+] GABA release by presynaptic GABAB receptors in rat cerebrocortical synaptosomes. Neurochemistry International, 27, 397–406.
Santos, M. L., Mota-Miranda, A., Alves-Pereira, G. A., Correia, J., & Marçal, N. (2004). Intrathecal baclofen for the treatment of tetanus. Clinical Infectious Diseases, 38, 321–328.
Sasaki, N., & Ogiwara, M. (2016). Intrathecal baclofen therapy in a child with severe scoliosis. Report of 2 cases. Neuromodulation, 19(6), 664–666. doi:10.1111/ner.12449.
Sawynok, J., & LaBella, F. S. (1982). On the involvement of GABA in the analgesia produced by baclofen, muscimol and morphine. Neuropharmacology, 21, 397–404.
Scheinberg, A., Hall, K., Lam, L. T., & O’Flaherty, S. (2006). Oral baclofen in children with cerebral palsy: A double-blind cross-over pilot study. Journal of Paediatrics and Child Health, 42, 715–720.
Schuler, V., Luscher, C., Blanchet, C., Klix, N., Sansig, G., Klebs, K., et al. (2001). Epilepsy, hyperalgesia, impaired memory, and loss of pre- and post-synaptic GABAB responses in mice lacking GABAB1. Neuron, 31, 47–58.
Sharma, R. C. (2015). Successful treatment of idiopathic intractable hiccup with baclofen and supportive treatment: A case report. Journal of Neuropsychiatry and Clinical Neurosciences, 27, e62–e63.
Shoptaw, S., Yang, X., Rotheram-Fuller, E. J., Hsieh, Y. C., Kintaudi, P. C., Charuvastra, V. C., et al. (2003). Randomized placebo-controlled trial of baclofen for cocaine dependence: Preliminary effects for individuals with chronic patterns of cocaine use. Journal of Clinical Psychiatry, 64, 1440–1448.
Silbert, P. L., Matsumoto, J. Y., McManis, P. G., Stolp-Smith, K. A., Elliott, B. A., & McEvoy, K. M. (1995). Intrathecal baclofen therapy in stiff-man syndrome: A double-blind, placebo-controlled trial. Neurology, 45, 1893–1897.
Smith, C. R., La Rocca, N. G., Giesser, B. S., & Scheinberg, L. C. (1991). High-dose oral baclofen: Experience in patients with multiple sclerosis. Neurology, 41, 1829–1831.
Snodgrass, S. R. (1992). GABA and epilepsy: Their complex relationship and the evolution of our understanding. Journal of Child Neurology, 7, 77–86.
Stackman, R. J., & Walsh, T. J. (1994). Baclofen reduces dose related working memory impairments after intraseptal injection. Behavioral and Neural Biology, 61, 181–185.
Stayer, C., Tronnier, V., Dressnandt, J., Mauch, E., Marquardt, G., Rieke, K., et al. (1997). Intrathecal baclofen therapy for stiff-man syndrome and progressive encephalomyeopathy with rigidity and myoclonus. Neurology, 49, 1591–1597.
Steger, M., Schneemann, M., & Fox, M. (2015). Systemic review: The pathogenesis and pharmacological treatment of hiccups. Alimentary Pharmacology & Therapeutics, 42, 1037–1050.
Suzdak, P. D., & Gianutsos, G. (1986). Effect of chronic imipramine or baclofen on GABAB binding and cyclic AMPproduction in cerebral cortex. European Journal of Pharmacology, 131, 129–133.
Taylor, M., & Bates, C. P. (1979). A double-blind crossover trial of baclofen- a new treatment for the unstable bladder syndrome. British Journal of Urology, 51, 504–505.
Teichgraber, L. A., Lehmann, T. N., Meencke, H. J., Weiss, T., Nitsch, R., & Deisz, R. A. (2009). Impaired function of GABAB receptors in tissues from pharmacoresistant epilepsy patients. Epilepsia, 50, 1697–1716.
Teoh, H., Malcangio, M., & Bowery, N. G. (1996). The effects of novel GABAB antagonists on the release of amino acids from spinal cord of the rat. British Journal of Clinical Pharmacology, 118, 1153–1160.
Thompson, A. N., Ehret Leal, J., & Brzezinski, W. A. (2014). Olanzapine and baclofen for the treatment of intractable hiccups. Pharmacotherapy, 34, e4–e8.
Turkyilmaz, A., & Eroglu, A. (2008). Use of baclofen in the treatment of esophageal stent-related hiccups. Annals of Thoracic Surgery, 85, 328–330.
Twycross, R. (2003). Baclofen for hiccups. American Journal of Hospice & Palliative Care, 20, 262.
Upton, N., & Blackburn, T. (1997). Pharmacology of mammalian GABAA receptors. In S. J. Enna & N. G. Bowery (Eds.), The GABA receptors (pp. 83–120). Totowa, NJ: Humana.
Vakil, N., van Zanten, S. V., Kahrilas, P., Dent, J., Jones, R., & Global Consensus Group. (2006). The Montreal definition and classification gastroesophageal reflux disease: A global evidence-based consensus. American Journal of Gastroenterology, 101, 1900–1920.
Van Bree, J. B., Audus, K. I., & Borchardt, R. T. (1988). Carrier-mediated transport of baclofen across monolayers of bovine brain endothelial cells in primary culture. Pharmaceutical Research, 5, 369–371.
Van Bree, J. B., Heijligers-Feijen, C. D., De Boer, A. G., Danhof, M., & Breimer, D. D. (1991). Stereoselective transport of baclofen across the blood-brain barrier in rats as determined by the unit impulse response methodology. Pharmaceutical Research, 8, 259–262.
Vaught, J. L., Pelley, K., Costa, L. G., Setler, P., & Enna, S. J. (1985). A comparison of the antinociceptive responses to the GABA-receptor agonists THIP and baclofen. Neuropharmacology, 24, 211–216.
Vienne, J., Bettler, B., Franken, P., & Tafti, M. (2010). Differential effects of GABAB receptor subtypes, {gamma}-hydroxybutyric Acid, and Baclofen on EEG activity and sleep regulation. Journal of Neuroscience, 30, 14194–14204.
Wagner, P. G., & Deakin, M. S. (1993). GABAB receptors are coupled to a barium-sensitive outward rectifying potassium conductance in premotor respiratory neurons. Journal of Neurophysiology, 69, 286–289.
Whelan, J. L. (1980). Baclofen in treatment of the “stiff-man” syndrome. Archives of Neurology, 37, 600–601.
Wiklund, I. (2004). Review of the quality of life and burden of illness in gastroesophageal reflux disease. Digestive Diseases, 22, 108–114.
Wilson, P. R., & Yaksh, T. L. (1978). Baclofen is anti-nociceptive in the intrathecal space of animals. European Journal of Pharmacology, 51, 323–330.
Wu, Y., Chan, K. F., Eubanks, J. H., Guin Ting Wong, C., Cortez, M. A., Shen, L., et al. (2007). Transgenic mice over-expressing GABA(B)R1a receptors acquire an atypical absence epilepsy-like phenotype. Neurobiology of Disease, 26, 439–451.
Wu, L. G., & Saggau, P. (1995). GABAB receptor-mediated presynaptic inhibition in guinea-pig hippocampus is caused by reduction of presynaptic Ca2+influx. Journal of Physiology, 485, 649–657.
Xi, Z. X., & Stein, E. A. (1999). Baclofen inhibits heroin self-administration behavior and mesolimbic dopamine release. Journal of Pharmacol and Experimental Therapeutics, 290, 1369–1374.
Xu, J., & Wojcik, W. J. (1986). Gamma aminobutyric acid B receptor-mediated inhibition of adenylate cyclase in cultured cerebellar granule cells: Blockade by islet-activating protein. Journal of Pharmacol and Experimental Therapeutics, 239, 568–573.
Xu, X. H., Yang, Z. M., Chen, Q., Yu, L., Liang, S. W., Lv, H. J., et al. (2013). Therapeutic efficacy of baclofen in refractory gastroesophageal reflux-induced chronic cough. World Journal of Gastroenterology, 19, 4386–4392.
Zemoura, K., Ralvenius, W. T., Malherbe, P., & Benke, D. (2016). The positive allosteric GABAB receptor modulator rac-BHFF enhances baclofen-mediated analgesia in neuropathic rats. Neuropharmacology, 108, 172–178.
Zerman, A., Hoefeijzers, S., Milton, F., Dewar, M., Carr, M., & Streatfield, C. (2016). The GABAB receptor agonist baclofen contributes to three distinct varieties of amnesia in the human brain—A detailed case report. Cortex, 74, 9–19.
Zhang, C., Zhang, R., Zhang, S., Xu, M., & Zhang, S. (2014). Baclofen for stroke patients with persistent hiccups: A randomized, double-blind, placebo-controlled trial. Trials, 15, 295.
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Bowery, N.G. (2016). Baclofen: Therapeutic Use and Potential of the Prototypic GABAB Receptor Agonist. In: Colombo, G. (eds) GABAB Receptor. The Receptors, vol 29. Humana Press, Cham. https://doi.org/10.1007/978-3-319-46044-4_17
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