Developing analgesics by enhancing spinal inhibition after injury: GABAA receptor subtypes as novel targets

The use of genetically-engineered mice has identified alpha 2- and alpha 3-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 nonselective or full GABA(A) receptor modulators indicates that in addition to involvement of specific subunits per se, the level of efficacy at individual a 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.