A question of balance – Positive versus negative allosteric modulation of GABAA receptor subtypes as a driver of analgesic efficacy in rat models of inflammatory and neuropathic pain

After injury GABAA receptor positive allosteric modulators (PAMs) mediate robust analgesia in animals via putative restoration of post-synaptic GABAA-α2 and -α3 receptor function within the spinal cord. GABA can also act at GABAA receptors localized on primary afferent neurones to inhibit presynaptic neurotransmitter release and produce analgesia via a process called primary afferent depolarization (PAD). Some forms of injury might sufficiently enhance PAD to shift it into a net excitatory process. Thus, negative allosteric modulators (NAMs) might also possess analgesic activity. We have compared compounds capable of either positively or negatively modulating GABAA receptors in rat models associated with injury-induced central sensitization. The subtype-selective PAMs NS11394 (1–10 mg/kg) and TPA023 (3–30 mg/kg) attenuated formalin-induced nocifensive behaviours. Similarly, both compounds reversed hindpaw mechanical hypersensitivity and weight bearing deficits in carrageenan-inflamed and nerve-injured rats. The non-selective PAM diazepam (1–5 mg/kg) was ineffective in all models. Surprisingly, both the non-selective NAM FG-7142 (3–30 mg/kg) and the α5-selective NAM α5IA-II (10–60 mg/kg) also attenuated formalin-induced nocifensive behaviours. In carrageenan-inflamed rats α5IA-II reversed mechanical hypersensitivity and weight bearing deficits whilst FG-7142 only attenuated weight bearing deficits. This picture was essentially reversed in nerve-injured rats for these two NAMs. With the exception of NS11394, all compounds attenuated exploratory motility behaviour in rats, either as a consequence of sedative or anxiogenic-like side-effects. These data indicate that the preferred selectivity and activity profiles for mediating analgesia upon activation of GABAA receptors might be more complex than previously anticipated, and is worthy of further exploration.

► We compare GABAA receptor positive and negative allosteric modulator (PAM and NAM) effects on rat pain behaviours.
► Both PAMs and NAMs have analgesic effects in inflammatory and neuropathic models.
► PAM and NAM analgesia reflects post- versus presynaptic actions at spinal GABAA receptors.
► Compounds with combined subtype-selective PAM and NAM activity could provide superior analgesia.
► Combined PAM and NAM activity could also alleviate comorbid anxiety and cognitive dysfunction.