Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter within the brain regulating neuronal excitability through a family of GABA receptors including GABA_A. Despite preclinical evidence, GABA_A receptor agonists are antinociceptive (Kendall et al., 1982; Malan et al., 2002) the GABA_A receptor is largely untargeted to develop analgesics due to the concomitant sedative, anesthetic, and amnestic effects occurring with orthosteric drugs, such as midazolam, that bind to the GABA_A receptor active site.

Structurally, the GABA_A receptor is composed of six different subtypes spanning α1 through α6. The α2 and α3 subtypes produce sedation, and in particular, the α2 subtype of the GABA_A receptor also contributes toward anxiolysis. This is opposed to α subtypes of the GABA_A receptor that when activated contribute toward anesthesia or amnesia (Fig. 1). Therefore, allosteric modulation of the GABA_A receptor presents an opportunity to develop small molecules to specifically target GABA_A subtypes that lead to analgesic effects while potentially leaving other GABA_A receptor subtypes unopposed.

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Fig. 1.

The GABA_A receptor and subtypes. (A) The GABA_A receptor is a ligand-mediated chloride channel. The GABA_A receptor subtypes form pentameric combinations composed of 19 different subunits, including α, β, γ, δ, ε, π, θ, and ρ. B. The majority of GABA_A receptors consist of 2 α, 2 β, and 1 γ subunit. C. In particular, the α1-α3 and α5 subtypes respond to classical benzodiazepines such as midazolam as opposed to the α4 and α6 subunits, which are insensitive (*). The α5 subunit is mainly expressed within the hippocampus, contributing to memory impairment after general anesthesia, and the α6 subunit is mainly expressed within the cerebellum.

In this regard, Lewter and colleagues within this issue of JPET describe how targeting the α2/α3 subunit of the GABA_A receptor with selective positive allosteric modulators (PAMs) may be a solution to targeting the GABA_A receptor to provide analgesia without amnesia or anesthesia (Lewter et al., 2024). The authors find that the GABA_A PAMs, KRM-II-81, and NS16085 provide antinociceptive qualities in a dose- and time-dependent manner when male Sprague–Dawley rats are subjected to complete Freund's adjuvant or chronic nerve constriction models. The behavioral studies conducted also highlighted the differences between the α2/α3 PAMs and midazolam, illustrating that the α2/α3 PAMs for the GABA_A receptor, unlike midazolam, produced analgesia without unwanted side effects such as amnesia. Further, the GABA_A antagonist flumazenil prevented the antinociceptive effects previously detected with KRM-II-81, NS-16085, and midazolam, demonstrating the antinociceptive effects of GABA_A receptor PAMs are specific to the GABA_A receptor. Taken together, this data identifies that KRM-II-81 and NS-16085 have the potential for modulating nociception via the GABA_A α2/α3 subtypes without amnesia or anesthesia, opening the door to developing drugs that can precisely modify the GABA_A receptor to treat pain.

Developing GABA_A α2/α3 PAMs to treat pain shows tremendous promise. The extensive knowledge of how the GABA_A receptor impacts behavior may provide an advantage when developing selective modulators for GABA_A subtypes as compared to research focused on developing nonopioid pain therapeutics for other targets (Giancotti et al., 2024; Sato et al., 2024; Stuertz et al., 2023; Zambelli and Gross, 2023; Angelia et al., 2023). However, as the study by Lewter only used male rodents, the importance of identifying potential differences in female and in aged rodent models cannot be underscored, as there are notable differences in GABA_A subunit expression, including α2/α3 that are sex- and age-dependent (Pandya et al., 2019). Also, KRM-II-81 and NS16085 had no impact on thermal hyperalgesia, which is important to understand further as newly developed drugs such as the α2/α3 GABA_A PAMs should ideally provide a similar analgesic profile as opioids to replace them.

As translating α2/α3 GABA_A receptor PAMs for use in humans is the ultimate goal, several other factors must be considered when developing these and other drugs to treat chronic pain. As multimodal approaches to analgesia are frequently used, understanding how treatment with α2/α3 PAMs may impact dosing with other analgesics that have sedative properties, such as gabapentin, should be considered. Further, the GABA_A receptor is the primary target that induces the hypnotic state for intravenous anesthetics (Forman and Miller, 2016), volatile anesthetics (Woll et al., 2018), and alcohol (Lobo and Harris, 2008). As such, the use of GABA_A PAMs to treat chronic pain should examine at a minimum whether there are additive sedative effects when combined with alcohol. When using α2/α3 GABA_A receptor PAMs to treat chronic pain, determining whether tolerance may occur with long-term treatment is also needed. Developing tolerance to analgesia would require escalated doses of α2/α3 GABA_A receptor PAMs, which may lead to unwanted effects such as amnesia or anesthesia. The addictive properties of PAMs should also be considered with preclinical assessment by conditioned place preference or self-administration. Tests should also be considered to assess whether physical dependence occurs with long-term use and whether abruptly stopping PAMs after chronic use could lead to withdrawal. Even within the context of these additional questions that will need to be addressed prior to translation, the findings of Lewter et al. are an exciting idea that can lead the way to developing drugs targeting specific subtypes of the GABA_A receptor to treat pain.

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