A PK/PD study on antihyperalgesia by an α2/3‐GABA A receptor PAM in mice: Lack of tolerance liability and potential involvement of γ1‐GABA A receptors

Abstract Background and Purpose GABA A receptors (GABA A Rs) are heteropentameric ion channels that control almost all CNS functions, including spinal nociception. Most GABA A Rs contain a γ2 subunit but differ in their α and β subunit composition. TPA023B is an α2/α3 subtype selective, non‐sedative, positive allosteric modulator (PAM) with antihyperalgesic activity in rodents. The pharmacokinetic/pharmacodynamic (PK/PD) characteristics of its antihyperalgesic action are unknown. Experimental Approach To establish the PK/PD relationship for the antihyperalgesic effects of TPA023B, blood and brain concentrations, and brain and spinal cord receptor occupancies (RO) were determined at various time points following the administration of single oral doses of TPA023B in mice, and correlated with the antihyperalgesic effects (increases in paw withdrawal thresholds to punctate mechanical stimuli). In addition, the potentiating effects of TPA023B on recombinant γ1‐ and γ2‐containing GABA A Rs (γ1‐GABA A Rs and γ2‐GABA A Rs, respectively) were determined in electrophysiological (patch‐clamp) and fluorometric (membrane potential‐sensitive dye) assays. Key Results Antihyperalgesic effects of TPA023B correlated well with blood and brain concentrations, and no signs of tolerance (clockwise hysteresis) were observed. However, antihyperalgesia did not correlate with receptor occupancy at γ2‐GABA A Rs, suggesting that a relevant part of the antihyperalgesic action occurred through non‐γ2‐GABA A Rs. In this regard, experiments in heterologous expression systems revealed that TPA023B not only potentiates γ2 but also γ1 containing GABA A Rs. Conclusions and Implications Antihyperalgesic effects of TPA023B do not undergo tolerance development. Besides γ2‐GABA A Rs, γ1‐GABA A Rs appear to contribute to the antihyperalgesic effects of TPA023B. γ1‐GABA A R selective PAMs may hence have a therapeutic potential in chronic pain conditions.