The use of genetically-engineered mice has identified α2- and α3-subunit containing GABA_A receptors as principal contributors to the spinal disinhibition that occurs after inflammation and neuropathic injury. Pharmacological comparison of subtype selective allosteric modulators such as NS11394 and L838417 with either non-selective or full GABA_A receptor modulators indicates that in addition to involvement of specific subunits per se, the level of efficacy at individual α subunits appears to be a critical determinant of analgesic activity. Combined, these complementary approaches identify the restoration of spinal inhibition after inflammatory, and especially neuropathic injury (the primary focus of this article), as a possible unifying mechanism for providing analgesia in patients with chronic pain.