GABA(B) receptor-mediated selective peripheral analgesia by the non-proteinogenic amino acid, isovaline
- PMID:22525135
- DOI: 10.1016/j.neuroscience.2012.04.026
GABA(B) receptor-mediated selective peripheral analgesia by the non-proteinogenic amino acid, isovaline
Abstract
Peripherally restricted analgesics are desirable to avoid central nervous system (CNS) side effects of opioids. Nonsteroidal anti-inflammatory drugs produce peripheral analgesia but have significant toxicity. GABA(B) receptors represent peripheral targets for analgesia but selective GABA(B) agonists like baclofen cross the blood-brain barrier. Recently, we found that the CNS-impermeant amino acid, isovaline, produces analgesia without apparent CNS effects. On observing that isovaline has GABA(B) activity in brain slices, we examined the hypothesis that isovaline produces peripheral analgesia mediated by GABA(B) receptors. We compared the peripheral analgesic and CNS effect profiles of isovaline, baclofen, and GABA (a CNS-impermeant, unselective GABA(B) agonist). All three amino acids attenuated allodynia induced by prostaglandin E2 injection into the mouse hindpaw and tested with von Frey filaments. The antiallodynic actions of isovaline, baclofen, and GABA were blocked by the GABA(B) antagonist, CGP52432, and potentiated by the GABA(B) modulator, CGP7930. We measured Behavioural Hyperactivity Scores and temperature change as indicators of GABAergic action in the CNS. ED(95) doses of isovaline and GABA produced no CNS effects while baclofen produced substantial sedation and hypothermia. In a mouse model of osteoarthritis, isovaline restored performance during forced exercise to baseline values. Immunohistochemical staining of cutaneous layers of the analgesic test site demonstrated co-localization of GABA(B1) and GABA(B2) receptor subunits on fine nerve endings and keratinocytes. Isovaline represents a new class of peripherally restricted analgesics without CNS effects, mediated by cutaneous GABA(B) receptors.
Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.
Similar articles
- Group II metabotropic glutamate receptor antagonism prevents the antiallodynic effects of R-isovaline.Asseri KA, Puil E, Schwarz SK, MacLeod BA.Asseri KA, et al.Neuroscience. 2015 May 7;293:151-6. doi: 10.1016/j.neuroscience.2015.02.022. Epub 2015 Feb 18.Neuroscience. 2015.PMID:25701709
- R-Isovaline: a subtype-specific agonist at GABA(B)-receptors?Cooke JE, Mathers DA, Puil E.Cooke JE, et al.Neuroscience. 2012 Jan 10;201:85-95. doi: 10.1016/j.neuroscience.2011.10.049. Epub 2011 Nov 4.Neuroscience. 2012.PMID:22079439
- Differential effects of R-isovaline and the GABAB agonist, baclofen, in the guinea pig ileum.Fung T, Asseri KA, Asiri YI, Wall RA, Schwarz SKW, Puil E, MacLeod BA.Fung T, et al.Eur J Pharmacol. 2016 Nov 15;791:85-90. doi: 10.1016/j.ejphar.2016.08.005. Epub 2016 Aug 10.Eur J Pharmacol. 2016.PMID:27521870
- Peripherally-acting opioids.Smith HS.Smith HS.Pain Physician. 2008 Mar;11(2 Suppl):S121-32.Pain Physician. 2008.PMID:18443636Review.
- Peripherally acting opioids and clinical implications for pain control.Sehgal N, Smith HS, Manchikanti L.Sehgal N, et al.Pain Physician. 2011 May-Jun;14(3):249-58.Pain Physician. 2011.PMID:21587328Review.
Cited by
- Use of Baclofen Premedication as an Analgesic Adjuvant in Patients Undergoing Percutaneous Nephrolithotripsy: A Placebo-Controlled, Double-Blind Randomized Trial.Mandabach M, Deichmann P, Massoll A, Graves S, Assimos D, Wood K, Ness TJ.Mandabach M, et al.Cureus. 2024 Jul 10;16(7):e64235. doi: 10.7759/cureus.64235. eCollection 2024 Jul.Cureus. 2024.PMID:39130904Free PMC article.
- GABA pharmacology: the search for analgesics.McCarson KE, Enna SJ.McCarson KE, et al.Neurochem Res. 2014 Oct;39(10):1948-63. doi: 10.1007/s11064-014-1254-x. Epub 2014 Feb 15.Neurochem Res. 2014.PMID:24532294Review.
- Peripheral Mechanisms of Neuropathic Pain-the Role of Neuronal and Non-Neuronal Interactions and Their Implications for Topical Treatment of Neuropathic Pain.Kocot-Kępska M, Zajączkowska R, Mika J, Wordliczek J, Dobrogowski J, Przeklasa-Muszyńska A.Kocot-Kępska M, et al.Pharmaceuticals (Basel). 2021 Jan 20;14(2):77. doi: 10.3390/ph14020077.Pharmaceuticals (Basel). 2021.PMID:33498496Free PMC article.Review.
- GABAB Receptors and Pain.Benke D.Benke D.Curr Top Behav Neurosci. 2022;52:213-239. doi: 10.1007/7854_2020_130.Curr Top Behav Neurosci. 2022.PMID:32812203Review.
- A commentary on modelling osteoarthritis pain in small animals.Malfait AM, Little CB, McDougall JJ.Malfait AM, et al.Osteoarthritis Cartilage. 2013 Sep;21(9):1316-26. doi: 10.1016/j.joca.2013.06.003.Osteoarthritis Cartilage. 2013.PMID:23973146Free PMC article.Review.
Publication types
MeSH terms
Substances
Related information
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Molecular Biology Databases