Analgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABA(A) receptor subtype

Agonists at the benzodiazepine-binding site of GABA(A) receptors (BDZs) enhance synaptic inhibition through four subtypes (α1, α2, α3 and α5) of GABA(A) receptors (GABA(A)R). When applied to the spinal cord, they alleviate pathological pain; however, insufficient efficacy after systemic administration and undesired effects preclude their use in routine pain therapy. Previous work suggested that subtype-selective drugs might allow separating desired antihyperalgesia from unwanted effects, but the lack of selective agents has hitherto prevented systematic analyses. Here we use four lines of triple GABA(A)R point-mutated mice, which express only one benzodiazepine-sensitive GABA(A)R subtype at a time, to show that targeting only α2GABA(A)Rs achieves strong antihyperalgesia and reduced side effects (that is, no sedation, motor impairment and tolerance development). Additional pharmacokinetic and pharmacodynamic analyses in these mice explain why clinically relevant antihyperalgesia cannot be achieved with nonselective BDZs. These findings should foster the development of innovative subtype-selective BDZs for novel indications such as chronic pain.