A novel GABAB receptor positive allosteric modulator, ASP8062, exerts analgesic effects in a rat model of fibromyalgia
Abstract
The gamma-aminobutyric acid type B (GABA B) receptor agonist, the sodium salt of gamma-hydroxybutyrate (GHB), significantly improved pain, sleep disturbance and fatigue in fibromyalgia (FM) patients. However, the use of GABA B receptor agonists is limited by their undesirable side-effects. To clarify whether GABA B receptor positive allosteric modulator (PAM) approach would achieve analgesia with less side-effects than GABA B receptor agonist in FM, we investigated the potential of a novel GABA B receptor PAM, ASP8062, for FM treatment. We examined the in vitro profiles of ASP8062, the effects of a GABA B receptor PAM and an agonist on pain in a rat model of FM, and the sleep/wake cycle, EEG during sleep stages and motor coordination in rats. ASP8062 showed PAM activity on human and rat GABA B receptors. Oral administration of ASP8062 significantly reversed the decrease in muscle pressure threshold in reserpine-induced myalgia rats. The analgesic effects of ASP8062 were significantly blocked by a GABA B receptor antagonist. ASP8062 had a significant effect on motor coordination at a 1000-fold higher dose than the analgesic dose in rats. ASP8062 significantly decreased total REM sleep time and frequency of sleep interruptions, and increased the power in delta waves frequency during non-REM sleep in rats. ASP8062, a novel GABA B receptor PAM, has therapeutic potential to exert analgesic effects with less side-effects compared to GABA B receptor agonists in patients with FM.
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In an animal study comparing ASP8062 and baclofen in male and female rats, both compounds reduced alcohol consumption in both genders, with ASP8062 more effective in males and baclofen having a greater impact on females.
“In a recent animal study comparing ASP8062 and baclofen in male and female rats to evaluate their effects on alcohol self-administration, both compounds demonstrated a reduction in alcohol consumption in both genders. Notably, ASP8062 was more effective in males, while baclofen had a greater impact on females.”
From A Narrative Review of Current and Emerging Trends in the Treatment of Alcohol Use Disorder (2024) · cites this paper as [59]
Cites
The rat brain in stereotaxic coordinates
Palkovits, M. (1983) · Neuropeptides · doi:10.1016/0143-4179(83)90049-5 · Cited by 28,959 · see citing works
The Rat Brain in Stereotaxic Coordinates
Paxinos, G., & Watson, C. (1983) · Elsevier eBooks · doi:10.1016/c2009-0-63235-9 · Cited by 28,585 · see citing works
Two-Process Model of Sleep Regulation
Binder, M. D., Hirokawa, N., & Windhorst, U. (2008) · Springer eBooks · doi:10.1007/978-3-540-29678-2_6166 · Cited by 3,895 · see citing works
Moldofsky, H., Scarisbrick, P., England, R. W., & SMYTHE, H. A. (1975) · Psychosomatic Medicine · doi:10.1097/00006842-197507000-00008 · Cited by 851 · see citing works
Bowery, N. G., Bettler, B., Froestl, W., Gallagher, J. P., Marshall, F. H., Raiteri, M., Bonner, T. I., & Enna, S. J. (2002) · Pharmacological Reviews · doi:10.1124/pr.54.2.247 · Cited by 601 · see citing works
Russell, I. J., Værøy, H., Javors, M. A., & Nyberg, F. (1992) · Arthritis & Rheumatism · doi:10.1002/art.1780350509 · Cited by 546 · see citing works
Role of central dopamine in pain and analgesia
Wood, P. B. (2008) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.8.5.781 · Cited by 373 · see citing works
Mombereau, C., Kaupmann, K., Froestl, W., Sansig, G., van der Putten, H., & Cryan, J. F. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300413 · Cited by 348 · see citing works
Russell, I. J., Perkins, A. T., Michalek, J. E., & Oxybate SXB‐26 Fibromyalgia Syndrome Study Group (2008) · Arthritis & Rheumatism · doi:10.1002/art.24142 · Cited by 302 · see citing works
Nagakura, Y., Oe, T., Aoki, T., & Matsuoka, N. (2009) · Pain · doi:10.1016/j.pain.2009.05.024 · Cited by 261 · see citing works
Clinical Course of γ-Hydroxybutyrate Overdose
Chin, R. L., Sporer, K. A., Cullison‡, B., et al. (1998) · Annals of Emergency Medicine · doi:10.1016/s0196-0644(98)70230-6 · Cited by 247 · see citing works
A Benefit-Risk Assessment of Baclofen in Severe Spinal Spasticity
Dario, A., & Tomei, G. (2004) · Drug Safety · doi:10.2165/00002018-200427110-00004 · Cited by 224 · see citing works
Reduced insular γ‐aminobutyric acid in fibromyalgia
Foerster, B. R., Petrou, M., Edden, R. A. E., Sundgren, P. C., Schmidt‐Wilcke, T., Lowe, S. E., Harte, S. E., Clauw, D. J., & Harris, R. E. (2012) · Arthritis & Rheumatism · doi:10.1002/art.33339 · Cited by 212 · see citing works
The effects of sodium oxybate on clinical symptoms and sleep patterns in patients with fibromyalgia.
Scharf, M. B., Baumann, M. M., & Berkowitz, D. V. (2003) · PubMed · Cited by 201 · see citing works
Intramuscular injection of tumor necrosis factor-alpha induces muscle hyperalgesia in rats☆
Schäfers, M., Sorkin, L. S., & Sommer, C. (2003) · Pain · doi:10.1016/s0304-3959(03)00115-5 · Cited by 165 · see citing works
Cyclic alternating pattern: a new marker of sleep alteration in patients with fibromyalgia?
Rizzi, M., Sarzi‐Puttini, P., Atzeni, F., CAPSONI, F., Andreoli, A., Pecis, M., Colombo, S., Carrabba, M., & Sergi, M. (2004) · PubMed · Cited by 135 · see citing works
DeSantana, J. M., Cruz, K. M. L., & Sluka, K. A. (2013) · Arthritis Research & Therapy · doi:10.1186/ar4402 · Cited by 115 · see citing works
Russell, J. I., Holman, A. J., Swick, T. J., Alvarez-Horine, S., Wang, G., & Guinta, D. (2011) · Pain · doi:10.1016/j.pain.2010.12.022 · Cited by 103 · see citing works
Pathophysiologic mechanisms of fibromyalgia and its related disorders.
Bradley, L. A. (2008) · PubMed · Cited by 96 · see citing works
Chapter 13 Descending inhibitory systems
Pertovaara, A., & Almeida, A. (2006) · Handbook of clinical neurology · doi:10.1016/s0072-9752(06)80017-5 · Cited by 92 · see citing works
A single intrathecal injection of GABA permanently reverses neuropathic pain after nerve injury
Eaton, M. J., Martínez, M. Á. G., & Karmally, S. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01564-4 · Cited by 89 · see citing works
Robinson, D. M., & Keating, G. M. (2007) · CNS Drugs · doi:10.2165/00023210-200721040-00007 · Cited by 89 · see citing works
Allosteric Modulation of G Protein-Coupled Receptors
May, L. T., Avlani, V. A., Sexton, P. M., & Christopoulos, A. (2004) · Current Pharmaceutical Design · doi:10.2174/1381612043384303 · Cited by 85 · see citing works
Allosteric Modulators of GABAB Receptors: Mechanism of Action and Therapeutic Perspective
Pin, J., & Prézeau, L. (2007) · Current Neuropharmacology · doi:10.2174/157015907781695919 · Cited by 84 · see citing works
Effect of baclofen on sleep‐related periodic leg movements
Guilleminault, C., & Flagg, W. (1984) · Annals of Neurology · doi:10.1002/ana.410150304 · Cited by 79 · see citing works
Spaeth, M., Bennett, R. M., Benson, B. A., Wang, Y. G., Lai, C., & Choy, E. (2012) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2011-200418 · Cited by 69 · see citing works
Varga, V., Attila Gabor, S. I. K., Freund, T. F., & Kocsis, B. (2002) · Neuroscience · doi:10.1016/s0306-4522(01)00448-1 · Cited by 68 · see citing works
Malcangio, M. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.05.012 · Cited by 68 · see citing works
Clinical Potential of GABABReceptor Modulators
Ong, J. A., & Kerr, D. I. B. (2005) · CNS Drug Reviews · doi:10.1111/j.1527-3458.2005.tb00049.x · Cited by 59 · see citing works
Ulloor, J., Mavanji, V., Saha, S. G., Siwek, D. F., & Datta, S. (2004) · Journal of Neurophysiology · doi:10.1152/jn.01104.2003 · Cited by 52 · see citing works
Management of Fibromyalgia Syndrome: Review of Evidence
Okifuji, A., & Hare, B. D. (2013) · Pain and Therapy · doi:10.1007/s40122-013-0016-9 · Cited by 49 · see citing works
Allosteric modulation of Class C GPCRs: a novel approach for the treatment of CNS disorders
Engers, D. W., & Lindsley, C. W. (2013) · Drug Discovery Today: Technologies · doi:10.1016/j.ddtec.2012.10.007 · Cited by 45 · see citing works
Analgesic effects of novel lysophosphatidic acid receptor 5 antagonist AS2717638 in rodents
Murai, N., Hiyama, H., Kiso, T., et al. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.08.032 · Cited by 45 · see citing works
Self-citationMurai, N., Sekizawa, T., Gotoh, T., et al. (2015) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2015.11.008 · Cited by 39 · see citing works
Self-citationLehmann, A., Mattsson, J. P., Edlund, A., et al. (2003) · Neurochemical Research · doi:10.1023/a:1022353923578 · Cited by 37 · see citing works
Kalinichev, M., Girard, F., Haddouk, H., Rouillier, M., Riguet, E., Royer-Urios, I., Mutel, V., Lütjens, R., & Poli, S. M. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.11.016 · Cited by 29 · see citing works
A Review of Sodium Oxybate and Baclofen in the Treatment of Sleep Disorders
Brown, M. A., & Guilleminault, C. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211796197098 · Cited by 26 · see citing works
Endogenous pain modulation : descending inhibitory systems
Pertovaara, A., & Almeida, A. (2006) · Cited by 16 · see citing works
Fibromyalgia: Mechanisms, Current Treatment and Animal Models
Brederson, J., Jarvis, M. F., Honoré, P., et al. (2011) · Current Pharmaceutical Biotechnology · doi:10.2174/138920111798357258 · Cited by 16 · see citing works
Murai, N., Fushiki, H., Honda, S., Murakami, Y., Iwashita, A., Irie, M., Tamura, S., Nagakura, Y., & Aoki, T. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2014.12.065 · Cited by 14 · see citing works
Self-citationKannampalli, P., Poli, S.-M., Boléa, C., & Sengupta, J. N. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.08.023 · Cited by 14 · see citing works
Kalinichev, M., Donovan-Rodríguez, T., Girard, F., et al. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.11.056 · Cited by 13 · see citing works
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Burnette, E. M., Nieto, S. J., Grodin, E. N., Meredith, L. R., Hurley, B., Miotto, K., Gillis, A. J., & Ray, L. A. (2022) · Drugs · doi:10.1007/s40265-021-01670-3 · Cited by 169 · see citing works
Animal models of fibromyalgia: What is the best choice?
Brum, E. S., Becker, G., Fialho, M. F. P., & Oliveira, S. M. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107959 · Cited by 71 · see citing works
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Celik, M., Gold, M. S., & Fuehrlein, B. (2024) · Brain Sciences · doi:10.3390/brainsci14030294 · Cited by 25 · see citing works
Walzer, M., Marek, G. J., Wu, R., Nagata, M., & Han, D. (2020) · Clinical Pharmacology in Drug Development · doi:10.1002/cpdd.766 · Cited by 19 · see citing works
- Authors
- Murai, N., Kondo, Y., Akuzawa, S., Mihara, T., Shiraishi, N., Kakimoto, S., & Matsumoto, M.
- Affiliations
- Astellas Pharma (Japan) (JP)
- Corresponding author
- Murai, Nobuhito
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 2019-12
- Volume
- 865
- Pages
- 172750
- ISSN
- 0014-2999 (ISSN-L)
- OpenAlex
- W2982110959
- Cited by
- 34
- References
- 42
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 4 · 2023: 6 · 2022: 3 · 2021: 5 · 2020: 5
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Astellas Pharma
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Fibromyalgia and Chronic Fatigue Syndrome Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- GABAB receptors, positive allosteric modulators, fibromyalgia, analgesia, sleep disorders, REM sleep, delta oscillations, motor coordination, GABA-B receptor agonist, gamma-hydroxybutyric acid
- MeSH terms
- Allosteric Regulation, Analgesics, Animals, Calcium, Disease Models, Animal, Electroencephalography, Fibromyalgia, gamma-Aminobutyric Acid, Humans, Male, Morpholines, Pyrimidines, Reserpine, Sleep, Rats, Sprague-Dawley, Receptors, GABA-B, Muscle, Skeletal, HEK293 Cells, Myalgia
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