ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2014
Antihyperalgesia by α2-GABAA receptors occurs via a genuine spinal action and does not involve supraspinal sites.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 46 citations in OpenAlex.
- Analgesic potential of PF-06372865, an α2/α3/α5 subtype-selective GABABritish journal of anaesthesia · 2019Trial
- N-Demethylsinomenine Relieves Neuropathic Pain in Male Mice Mainly via Regulating α2-Subtype GABACNS neuroscience & therapeutics · 2025Article
- γ1 GABAThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Attenuation of Streptozotocin-Induced Diabetic Neuropathic Allodynia by Flavone Derivative Through Modulation of GABA-ergic Mechanisms and Endogenous Biomarkers.Neurochemical research · 2024Article
- Potential novel therapeutic strategies for neuropathic pain.Frontiers in molecular neuroscience · 2023Review
- GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAPharmacology & therapeutics · 2022Review
- Modulation of GABAFrontiers in molecular neuroscience · 2022Article
- Synergistic antihyperalgesic and antinociceptive effects of morphine and methyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate (MP-III-024): a positive allosteric modulator at α2GABAPsychopharmacology · 2021Article
- Article
- 8-Substituted Triazolobenzodiazepines:Frontiers in pharmacology · 2021Article
- Enhancing neuronal chloride extrusion rescues α2/α3 GABANature communications · 2020Article
- Effects of the α2/α3-subtype-selective GABAA receptor positive allosteric modulator KRM-II-81 on pain-depressed behavior in rats: comparison with ketorolac and diazepam.Behavioural pharmacology · 2019Article
- The α2,3-selective potentiator of GABAPharmacology, biochemistry, and behavior · 2019Article
- Itch suppression in mice and dogs by modulation of spinal α2 and α3GABANature communications · 2018Article
- Glycine receptors and glycine transporters: targets for novel analgesics?Cellular and molecular life sciences : CMLS · 2018Review
- Pharmacological and antihyperalgesic properties of the novel α2/3 preferring GABABrain research bulletin · 2017Article
- Neonatal bladder inflammation induces long-term visceral pain and altered responses of spinal neurons in adult rats.Neuroscience · 2017Article
- The clobazam metabolite N-desmethyl clobazam is an α2 preferring benzodiazepine with an improved therapeutic window for antihyperalgesia.Neuropharmacology · 2016Article
- New insights in the systemic and molecular underpinnings of general anesthetic actions mediated by γ-aminobutyric acid A receptors.Current opinion in anaesthesiology · 2016Review
- Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
Drugs that enhance GABAergic inhibition alleviate inflammatory and neuropathic pain after spinal application. This antihyperalgesia occurs mainly through GABAA receptors (GABAARs) containing α2 subunits (α2-GABAARs). Previous work indicates that potentiation of these receptors in the spinal cord evokes profound antihyperalgesia also after systemic administration, but possible synergistic or antagonistic actions of supraspinal α2-GABAARs on spinal antihyperalgesia have not yet been addressed. Here we generated two lines of GABAAR-mutated mice, which either lack α2-GABAARs specifically from the spinal cord, or, which express only benzodiazepine-insensitive α2-GABAARs at this site. We analyzed the consequences of these mutations for antihyperalgesia evoked by systemic treatment with the novel non-sedative benzodiazepine site agonist HZ166 in neuropathic and inflammatory pain. Wild-type mice and both types of mutated mice had similar baseline nociceptive sensitivities and developed similar hyperalgesia. However, antihyperalgesia by systemic HZ166 was reduced in both mutated mouse lines by about 60% and was virtually indistinguishable from that of global point-mutated mice, in which all α2-GABAARs were benzodiazepine insensitive. The major (α2-dependent) component of GABAAR-mediated antihyperalgesia was therefore exclusively of spinal origin, whereas supraspinal α2-GABAARs had neither synergistic nor antagonistic effects on antihyperalgesia. Our results thus indicate that drugs that specifically target α2-GABAARs exert their antihyperalgesic effect through enhanced spinal nociceptive control. Such drugs may therefore be well-suited for the systemic treatment of different chronic pain conditions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.