Behavioral Effects of α2/α3 Subtype‐Selective GABA_A Receptor Positive Allosteric Modulators

Abstract

Millions of individuals suffer from chronic pain. Opioids are effective for treating chronic pain but their use is limited due to undesirable side‐effects. Previous studies have shown that different subunits of the GABAA receptor are associated with different actions of the benzodiazepine site. While α2/α3 subunit‐containing GABAA receptors mediate antinociceptive effects, α1 subunit‐containing GABAA receptors mediate sedative and abuse‐related effects. This study sought to examine the behavioral effects of two α2/α3‐subtype selective PAMs: KRM‐II‐81 and NS16085. In a rat model of inflammatory pain (complete Freund's adjuvant) and a rat model of neuropathic pain (chronic constriction injury), both PAMs and the classical benzodiazepine midazolam attenuated mechanical hyperalgesia (as measured by von Frey test). In the procedure of food‐maintained operant responding, KRM‐II‐81 and NS16085 did not significantly decrease the response rate at doses that produced maximal antinociception. Contrastingly, midazolam significantly reduced the response rate at doses that attenuated mechanical hyperalgesia. In a horizontal wire test aimed to measure muscle relaxation, within the dose range that produced antinociception, only midazolam dose‐dependently increased the percentage of rats unable to grasp the wire, indicating muscle‐relaxant activity. These behavioral effects can be attenuated by benzodiazepine receptor antagonist flumazenil, confirming that the behavioral effects of these subtype‐selective GABAA PAMs are mediated through the benzodiazepine site of GABAA receptors. Taken together, while midazolam produced antinociceptive, rate‐suppressing, and muscle‐relaxant activity at similar doses, both subtype‐selective GABAA receptor PAMs selectively produced antinocicpetive effects. Collectively, these data support the notion of α2/α3‐subtype selective GABAA PAMs as novel analgesics.Support or Funding InformationR01DA034806This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.